Wilbur Sawyer returned to California in the spring of 1908, following a two-year medical residency at Massachusetts General Hospital. He had accepted a post at the University of California (UC) infirmary in Berkeley, and planned to establish a general medical practice within a few years. At UC he examined new students, vaccinated them against smallpox if needed, and tended the medical needs of UC students and staff. He also took on a small share of the practice of Dr. George Reinhardt, founder of the UC infirmary and chair of the Department of Hygiene, and covered many of his teaching and consulting duties during Reinhardt's frequent absences. These included assisting at the State Board of Health's Hygienic Laboratory (then located on the UC campus) and serving as expert physician to the "Poison Squad" of the Bureau of Chemistry at the U.S. Department of Agriculture. (The squad was then engaged in testing various food additives for safety, using themselves as experimental subjects. The Bureau of Chemistry later became the nucleus of the U.S. Food and Drug Administration.)

In 1910, in addition to his infirmary duties, Sawyer was appointed director of the State Hygienic Laboratory, a part-time position. In July 1911, the directorship was made full-time and Sawyer resigned from his infirmary job. The laboratory had been established in 1905 by the California State Board of Health to do bacteriological tests for California physicians and health officers, and was staffed by UC faculty. The laboratory tested samples for diphtheria, malaria, typhoid fever, tuberculosis, syphilis, gonorrhea, anthrax, and hookworm disease. They also examined water and milk samples for bacterial contamination. The State Board of Health had no separate staff to investigate epidemics and the Hygienic Laboratory soon assumed that responsibility as well, investigating outbreaks of bubonic plague, rabies, typhoid fever, and poliomyelitis.

The Hygienic Laboratory was part of a rapidly growing public health movement in the early 20th century. Armed with new scientific knowledge about microorganisms and the diseases they caused, public health officials were gradually organizing permanent, active boards of health at all levels. They were also developing and improving procedures for tracking infectious diseases and limiting their spread; increases in immigration, population expansion, and faster transportation had raised concerns about disease transmission. During his tenure as director, Sawyer carried out a number of these investigations, and improved contagious disease reporting--especially for venereal diseases--throughout the state. He also convinced the State Board of Health to establish a Pasteur Institute within the Hygienic Laboratory, to manufacture and administer rabies vaccine. Up to that time, physicians had to request the vaccine from the United States Public Health Service in Washington. By mid-1912, the laboratory was supplying all the vaccine virus for California public health work and had been certified by the U.S. Public Health Service.

The summer of 1911 brought one additional transition: Dr. Sawyer deepened his friendship with Margaret Henderson, a bacteriologist and sister of Sawyer's good friend Victor Henderson. Miss Henderson had served as chief assistant in the Hygienic Laboratory until 1908, when she was appointed an instructor in the Department of Hygiene. She had planned to attend Johns Hopkins School of Medicine in the fall of 1911; instead, she married Wilbur Sawyer.

Sawyer was appointed to the California State Board of Health and elected its secretary in September 1915. He resigned as director of the Hygienic Laboratory and moved his family to Sacramento. For the next several years he met with county and municipal health officers, conferred with officers of state-run institutions, met with representatives from industry and labor organizations about their health problems, gave public health lectures to professional and civic groups, and investigated outbreaks of smallpox and typhus fever. He also represented the California State Board of Health at meetings of national public health organizations, and in 1916 spent considerable time in Washington, D.C. and elsewhere, enlisting support for tuberculosis control bills being considered in the House and Senate, and testifying before the Senate Committee on Public Health and National Quarantine.

The U.S. entered World War I in April 1917, and, concerned about the "evil effects of liquor and vice among the soldiers," the Secretary of War called on public health officials to increase prevention and treatment measures for venereal diseases. California's State Board of Health responded quickly, establishing cooperative networks of military, county, and municipal officials, and organizing a conference to establish a statewide plan for venereal disease control. By August, a Bureau of Venereal Diseases had been established within the State Board of Health, with Sawyer as temporary director. This bureau coordinated venereal disease reporting, arranged quarantine and treatment for those diagnosed, established or expanded diagnostic and treatment facilities and set standards for them, and produced educational materials. Though the California program called for suppression of prostitution, it also attempted to rehabilitate prostitutes after they were treated. By December that year, Sawyer could report to a meeting of the Western Social Hygiene Association that the program was working very well.

Soon afterward, Sawyer accepted a commission as a major in the Medical Reserve Corps. He moved to Washington, D.C. in January 1918 to take up his duties in the Venereal Disease Section of the Surgeon General's Office, leaving his wife and three daughters behind in California. There he and fellow Californian William F. Snow compiled statistics on venereal disease incidence, treatment, and prevention in the army since early 1917. They showed that syphilis and gonorrhea cases outnumbered those of other serious communicable diseases, both in total number of cases and amount of disability caused. They also argued, however, that these were among the most preventable diseases if proper methods were applied. When the study finished in June, Sawyer was reassigned to Newport News, Virginia, to serve as Supervisor of Non-Military Activities. He spent the rest of the war as the military liaison assisting local authorities with programs to control vice and keep order in a town full of new army and navy recruits.