In early 1884, Search himself taught the first classes of the Philadelphia Textile School to five students at 1336 Spring Garden Street.

The school acquired the former Philadelphia Institute of the Deaf and Dumb on the corner of Broad and Spruce Streets, which allowed rapid expansion of academic offerings and capacity of students.

In 1942, the school was granted the right to award baccalaureate degrees and changed its name to the Philadelphia Textile Institute (PTI).

In 1949, having decided to break its ties with the museum, PTI moved to its present site in the East Falls section of Philadelphia.

The purchase of additional properties in East Falls in 1980 and 1988 nearly doubled the campus again, adding classrooms, research laboratories, student residences, and athletic facilities.

[11][13][14] An additional 10 Jefferson College trustees, including Joel Barlow Sutherland, were appointed to supervise the new facility from Philadelphia, owing to the difficulty of managing a medical department on the other side of the state.

[13] Two years later, this second board was granted authority to manage the Medical Department, while the Jefferson College trustees maintained veto power for major decisions.

[15] This building had an attached hospital, the second such medical school/hospital arrangement in the nation, servicing 441 inpatients and 4,659 outpatients in its first year of operation.

This collection of professors would institute numerous changes to Jefferson—including providing patient beds over a shop at 10th and Sansom Streets in 1844—and the staff would remain unchanged for 15 years.

[21] The renowned surgeon and Jefferson Medical College anatomy professor, William S. Forbes, was arrested for his role in the grave robbery but was acquitted[22] Forbes helped write the 1867 Pennsylvania Law named the "Anatomy Act" which called for hospitals, prisons and mental health wards to provide the bodies of those that had no family or funds for burial to medical schools for anatomical research.

[26] In 2023, university president Mark Tykocinski was criticized for liking tweets expressing controversial views about vaccinations and gender reassignment surgery for children.

The university's East Falls 100-acre (40 ha) wooded campus is located about eight miles northwest of Center City, Philadelphia, accessible by two of SEPTA's Regional Rail lines.

Jefferson sponsors 17 varsity intercollegiate teams: Men's sports include baseball, basketball, cross country, golf, soccer, tennis and track & field; while women's sports include basketball, cross country, golf, lacrosse, rowing, soccer, softball, tennis, track & field and volleyball.

The merged school chose to retain PhilaU's nickname and the athletic program follows the overall institution in using the branding of "Jefferson" when describing the university as a whole.