The first building constructed on the newly purchased property was to be the hospital's Main Building. Also known as "Block Building", it was designed and built following the strict guidelines established by Dr. Thomas Story Kirkbride. "Kirkbride Plan" hospitals, as they came to be known, were very common in the United States during the late 19th century. By the time Danville State Hospital was established in 1868, Pennsylvania already had two other Kirkbride Plan hospitals, one in Harrisburg and one in Dixmont. The Kirkbride Plan was so popular that the Association of Medical Superintendents of American Institutions for the Insane had even adopted the Kirkbride plan as their standard for all new hospitals for the insane.

Designed by Philadelphia architect John McArthur Jr., construction started on the original Kirkbride Plan building at Danville on August 26, 1869 with the laying of the cornerstone. Among the attendees for the cornerstone laying was Governor John W. Geary. Three years later, the still unfinished building opened on October 18, 1872. At the time of opening only the majority of the south wing and the administration section were completed. Work continued on the north wing through 1875. The finished building would come to a total of 1,143 feet in length. The four story (not including the attic, tower or basement) administration section contained seventy rooms. Including a library, chapel, auditorium, kitchen, dining room, sewing room, as well as administrative offices and a home for the superintendent and family.

When the building opened in 1872, the patient capacity of the hospital was only 250. The first patient didn't arrive at the hospital until three weeks after the opening. Over the following year 210 more patients were admitted, some of which were transferred from Harrisburg State Hospital to help alleviate their over crowding problem. By 1875 work was finishing up on the north wing, which once opened, would increase the patient capacity of the hospital to 750. The completed building featured state of the art amenities, including mechanical ventilation, fire hoses in every ward, and an ice chamber which was located in the basement for storage of meats, butter, milk, and fruit. Other store rooms in the basement housed bread and other provisions. The laundry featured new steam drying rooms. Each ward had it's own bath room and water closet. The exterior of the building featured a stone administration section with two large towers that rose above the main roof line. The wards were made of brick and covered in stucco. The floors were made of hardwood and the roof was covered in slate. On the roof of the wards were large cupolas, which assisted in ventilation of the building. The building was lighted by gas and heated by steam, both produced by a power plant located on site.

The first superintendent of the hospital was Solomon S. Schultz. Solomon had served as the first assistant to John Curwen at Harrisburg and had also been a surgeon at several Civil War hospitals. He served the hospital as superintendent for 23 years. During his time at the hospital he created Danville into a fine example of what a Kirkbride hospital should be. Not only was the building constructed according to Dr. Thomas Kirkbride's standards, but his attitude and the way Solomon regarded the patients was everything Dr. Kirkbride had strived for in his therapeutic methods. Treatment for patients at the new hospital consisted of rest, wholesome food, occupation, and diversion, with limited amounts of medicine. Early recreational activities were largely controlled and dependant upon the hospital staff. Some of the amusements for the patients consisted of concerts, reading, dances, picnics, carriage rides, games, trips to the county fair and theater, the showing of slides, and an in house library. There was a limited amount of occupational therapy in the hospital's early days. Female patients would make crafts and other items that would be sold, that money would then be use to purchase things like instruments, books, and sheet music. Picnics on the front lawn of the hospital were common in the early days of the hospital. As many as fifty to eighty patients would spend the afternoon outdoors. The picnics would consist of beef and ham sandwiches, rolls, butter, fruit spreads, pickles, peanuts, ice water, coffee, ice cream, and cake. After lunch the men would be allowed cigars and the women would receive a pinch of snuff.

Between 1888 and 1890, epidemics of dysentery and diarrhea occurred due to the contamination of the hospital's water supply. At that time the chief source of water for the hospital was directly from the river, about 100 feet in front of the hospital. Reportedly the contamination occurred as a result of floods and not as a result of the hospital sewage being piped into the river. Regardless, when the analysis of the river water returned unsafe for drinking, water was brought from a spring in a wooden tank mounted on a hand-drawn cart. Later a well was sunk on the property because the spring proved to be an inadequate source of water. In 1890 the pipe delivering raw sewage from the hospital to the river was moved 3,368 yards down stream to what was considered a "safe point" to deposit the sewage. In 1904 a water filtration plant was built to filter the water coming from the river. The filtration plant used a new York Continental Jewel Filtration Apparatus with was able to filter 320,000 gallons of water in 24 hours. A sewage plant was also constructed. Sewage was now piped to a 20,000 gallon concrete reservoir and then distributed to the fields by broad irrigation. Later in 1910 the sewage plant was upgraded and was then able to treat the sewage using chloride of lime before passing into a sedimentation tank and eventually to an adjoining stream. During the 1890s, reports commonly showed that beds were being made up in the corridors of the Main Building to accommodate an increasing over crowding problem.

Over the next sixty years the hospital grew by leap and bounds. Many new out buildings were constructed to expand the patient capacity of the hospital. Some of the new buildings were infirmaries for men and women, an industrial building for men and women, a male and female dormitory for outside employees, a male and female tuberculosis building, an annex to the female infirmary, a continued care building for male and female patients, a farm colony building, the hospital building, a laundry building, male and female nurses homes, a gate house, additional farm buildings, a fire house, a butcher shop, greenhouses, a power plant, a pumping station and a sewage disposal plant. Between 1904 and 1906 all the buildings at the hospital were wired with electricity, and new lighting fixtures were installed. This replaced the original gas light system.

Many more additions and improvements to the hospital were seen between 1912 and 1920. Some of these included more fire fighting equipment, upgraded electrical and machine shops, better heating systems were tested, and a laboratory was developed to enable water testing. An industrial building was constructed and used for occupational and vocational therapies, such as shoe repair, broom making, and a tailor shop. The new industrial program also helped to fund a new moving picture machine, which was installed in the hospital's amusement hall. The hospital provided it's own food at farms located on the hospital grounds. Much of the work done at the hospital and the farms was done by patients as part of the occupational therapy program. Patients that were able to work were encouraged to do things like shovel snow, maintain the lawns, plant flowers and trees, and raise crops and livestock. Female patients did much of the cooking, they also worked in the laundry and mended patient garments. This work was thought to give the patients a sense for purpose, it also kept them occupied, mentally and physically. The use of patient labor kept operating costs low at state run hospitals like Danville. At times patients would even help in the construction of new buildings. However in 1968 the "Institutional Peonage Abolishment Act" was passed. The law required that any patients working at the hospital was required to be paid. As a result, occupational therapy programs like farming were soon discontinued at almost all state hospitals in the United States, including Danville. New staff members had to be hired to maintain the grounds and work in the kitchens. This caused operating costs at the hospital to increase dramatically. No longer could excess crops and patient made crafts be sold at local markets. State hospitals like Danville were now forced to rely on state funds only, and there never seemed to be enough. During the peak of the state hospital system in the very early 1950s, Danville had a patient population of around 3,000. And it's annual operating cost was around $900,000.

The need for large state hospitals declined in the late twentieth century as a result of new medicines and methods of treatments. State hospitals all over the United States saw their patient populations fall rapidly through the 1970s 80s,and 90s. Deinstitutionalization, which was a movement to remove patients from hospitals and return them to home care environments also contributed to the falling number of patients at state institutions. Danville saw it's patient population plummet from 2,801 in 1955 to under 200 in 2008. Today (2009) the hospital is still a fully functioning mental treatment facility, focusing on long term care. The main building still looks almost exactly the same as it did over 100 years ago with a few minor alterations. The slate roof has been replaced with shingles and in 2008 the building received a face lift of new stucco to 75% of the exterior of the wings. The cupolas have also been painted and refurbished. Smoking pavilions were built onto the rear of the building during the fifties. All the patients at the hospital are once again living almost exclusively in the Main Building. Vacant wards are being renovated into offices, drop ceilings are being installed and new tile floor is being laid down. The administration section of the building is still almost fully original. The intricate tile and wood work from when the building was first constructed still exists today. Stained glass still accents the upper floors of the administration section and the chapel also looks much the way it did years ago.