In the spring of 1884, Osler traveled to Europe to spend four months attending medical clinics and conferences, and catching up on the rapidly growing field of bacteriology in Berlin and Leipzig. While in Leipzig, he received a cable from Dr. James Tyson of the University of Pennsylvania Medical School, asking if he would be interested in taking the post of Professor of Clinical Medicine there. Osler said he would; though strongly attached to McGill, he could not pass up the opportunities available in Philadelphia. The University of Pennsylvania Medical School, founded in 1765, was the first in America; the city was also home to Pennsylvania Hospital (dating to 1751), several other large hospitals, and the Jefferson Medical College. After several months of vetting--the Philadelphia medical community was tightly-knit and the medical faculty had only once hired someone who was not a Pennsylvanian or an alumnus--Osler took up his new post in October 1884.

At Pennsylvania, he no longer taught preclinical courses, but was responsible for clinical lectures, ward rounds, and autopsies. The clinical teaching opportunities in Philadelphia hospitals were plentiful. Besides the University Hospital, Osler and his students had access to the large public hospital, almshouse, and asylum complex known as Blockley, which housed some two thousand patients. In the Blockley morgue, Osler did autopsies on afternoons and weekends with students. He also saw patients at the Orthopedic Hospital and Infirmary for Nervous Diseases. Probably because of the larger variety of cases, including neurological diseases, Osler's interests began shifting from pathology to clinical examination and therapeutics. He began doing studies of chorea, cerebral palsy, heart diseases, and malaria. He also had a thriving consulting practice, which included several visits to the poet Walt Whitman, then living in nearby Camden, New Jersey.

As in Montreal, Osler's energy, knowledge, and enthusiasm made him popular with both students and colleagues. He made many good friends and professional connections, and joined several local medical groups, including the College of Physicians of Philadelphia. He became close friends with neurologist S. Weir Mitchell, surgeon Samuel W. Gross, and gynecologist and surgeon Howard A. Kelly, among others. He also served as an editor for the Philadelphia Medical News. At medical meetings and in editorials he began taking a role as "medical statesman," addressing professional questions such as the standards of medical schools, medical licensing, raising funding for medical school expansion, and admitting women to regular medical schools. (Unlike many of his male colleagues, Osler was never hostile to the idea of women physicians--he occasionally taught students from the Women's Medical College of Pennsylvania--but he knew it would be extremely hard for women doctors to make a living, given the social and cultural constraints of that era. He believed that nursing was a more practical alternative for women interested in health care careers.) He also became a charter member of the Association of American Physicians, founded in 1885, whose aim was the advancement of science in medicine.

Though he enjoyed the clinical teaching opportunities, and the professional activities, Osler felt that the University of Pennsylvania was lagging behind other notable American medical schools such as Harvard. Pennsylvania had implemented some major reforms starting in 1877: adding a third year to the program, expanding the school terms, entrance exams, adding scientific subjects and laboratory work, and arranging courses in a graded sequence. The campus was moved from downtown Philadelphia to a new location several miles away, and included the new university hospital. But Osler found the laboratories to be inadequate, and the University Hospital small and unfinished. And although he could take his students on hospital ward rounds, Pennsylvania had not yet developed a clerkship requirement for senior students or a hospital organization that supported such clinical training. As a junior professor (and outsider) Osler wasn't in a position to effect the types of reform he had helped along in Montreal.

Thus, in 1888, when John Shaw Billings (director of the Surgeon General's Library and medical advisor to the Johns Hopkins trustees) asked Osler to come to the new Johns Hopkins Hospital in Baltimore, Osler was more than ready to join the most innovative medical education venture in history.