Osler had loved England since his postgraduate days in London, and had returned frequently over the years. As he got older, the pace of his life at Hopkins threatened to overwhelm him, and he began to yearn for an easier job. The Oslers had also considered moving to England as their son Revere grew, so that he could attend school there. In 1904, Oxford University's Regius Professor of Medicine, John Burdon Sanderson retired, and Osler was offered the post. Oxford had only recently revived its medical program, and the Regius Professorship, while not a sinecure, promised to be much less demanding than Osler's situation in Baltimore. The main duties were examining candidates for the MD degree after they had trained in London (Oxford had only a pre-clinical medical faculty). The Regius Professor was also a member of Christ Church College, a curator of the Bodleian Library, and a member of the governing bodies of the university and of the Oxford University Press. Not wishing to completely give up clinical work, Osler also gave weekly clinics for medical students and local doctors at Oxford's Radcliffe Infirmary. He became involved in efforts to improve and expand the medical school faculty and facilities, sometimes raising funds for various projects, such as a laboratory for the Radcliffe Infirmary. He also continued his public health work, founding the Oxfordshire County Association for the Prevention of Tuberculosis, and setting up a special tuberculosis dispensary in the Radcliffe which became a model for the country.

Even if officially semi-retired, Osler continued to publish steadily during his Oxford years. He worked on the seventh edition of The Principles and Practice of Medicine and edited a seven-volume System of Medicine featuring contributions by many leading experts (including himself). He published clinical articles, but also devoted much more time to studies in the history of medicine. Finally, he also had more leisure for searching out rare books for his own and others' libraries, and beginning a catalog of his huge personal book collection.

As Regius Professor and well-known physician, Osler was invited to sit on many committees and councils; the Oslers also received many social invitations and often entertained at their home. They also hosted an unending stream of visitors, including relatives, medical students, former students, and notables such as Rudyard Kipling and Mark Twain. (Osler jokingly called the house "the Open Arms.") Osler was also in demand as a consultant, although his consulting practice was far more limited than at Johns Hopkins.

In June 1911, the newly crowned George V created Osler a baronet, in recognition of his numerous contributions to medicine. Although Osler had always disliked title-hunters, and had privately told his wife that he would decline any title offered, he accepted the baronetcy, telling her, "Canada will be so pleased--there's only one Canadian baronet." To one friend he confided that though he was grateful for the hundreds of congratulations he received, "This thing cannot make us any happier, and as we were very contented before, I hope it will not disturb our Aequanimitas."

Although many years gone from Johns Hopkins, Osler kept in close contact with his friends there, and had an ongoing interest in developments at the medical school. When, in 1911, the Hopkins administration and faculty considered requiring clinical professors to become full-time (giving up their private practices), Osler vigorously supported those who opposed the change. His influence helped stall the new policy for several years, though it was finally adopted.

World War I

The Great War (World War I), which started in August 1914, put an end to the "delightful life and place" that Osler was enjoying so much. At the university, soldiers were lodged in some of the dormitories, one large hall became a hospital, and college infirmaries were turned into hospital branches. College wives, including Lady Osler, volunteered with the Red Cross, made hospital garments, and did other necessary work. Sir William was made an honorary colonel in the Oxfordshire militia, and soon held appointments at several nearby military hospitals. He was Physician-in-Chief at the Queen's Canadian Military Hospital at Shorncliffe, a consultant to the American Women's Auxiliary Hospital at Paignton, and head physician at the Canadian Red Cross Hospital in Cliveden. Aware that infectious diseases had caused more deaths than wounds had in recent military conflicts, he also gave addresses and wrote pamphlets for soldiers and civilians, urging attention to public health measures, including vaccination for typhoid fever.

Sir William's characteristic optimism and cheerfulness turned to grim pessimism during the first few months of the war. Like most observers, he was horrified by the Germans' militarism, especially their brutal treatment of the Belgians, and its implications for western civilization. During the first year, he and Lady Osler raised money to help the refugees from Belgium, and opened their home to them as well. As the war ground on, the Oslers' beloved only child, Revere, reached enlistment age and joined the McGill Hospital Unit in France. In 1916, he transferred to a Royal Field Artillery brigade, and was killed in action in Belgium on August 30, 1917. His parents resolved to be brave and carry on, to work through their pain with work and service, and as Osler said, " . . . take up what is left of life as though he were with us."

The war came to an end in 1918. Most of the Canadians and Americans gradually returned home, and Oxford life started getting back to normal. Osler continued work on his library cataloging and textbook revisions, and attended to his official duties and consultations. In the summer of 1919, shortly after his 70th birthday, he had a bout of bronchitis. Several months later he came down with a more severe respiratory infection, probably influenza. (The great influenza pandemic of 1918-1919 was not quite over.) He developed pneumonia, with pleurisy and lung abscesses during the next few months, and finally died on December 29, 1919. After the autopsy (which Osler had asked his friends to do) his remains were cremated and the ashes later interred in a niche at the Osler Library at McGill.

Sir William was widely and sincerely mourned, and memorials were written for many years after his death. As his friend J. G. Adami noted,