Noguchi was born at Okinashimamura in Japan. In spite of a humble family background and a physical handicap caused by a childhood accident, he pursued a career in medicine. After considerable perseverance he entered medical school in Tokyo, obtaining his diploma in 1897. Three years later he traveled to America and commenced work at the University of Pennsylvania, studying animal venoms and their antivenins. In 1904, after a year spent in Copenhagen, Noguchi joined the Rockefeller Institute for Medical Research, New York. Here he successfully cultured the spirochete bacterium, Treponema pallidum, which causes syphilis. This enabled Noguchi to devise a diagnostic skin test for syphilis using an emulsion of his spirochete culture. He further showed that T. pallidum invades the nervous system as the disease progresses. In recognition of his work, Noguchi was awarded the Order of the Rising Sun in his home country in 1915.

Noguchi went on to study the possible causes of other diseases. After investigating Oroya fever in South and Central America, he showed that it was caused by a bacterium, Bartonella bacilliformis, which was transmitted to humans by sand flies. Between 1919 and 1922, Noguchi became certain that yellow fever also was caused by a bacterium. However, by 1927 this view had been discredited with the discovery that a virus was responsible.

In the same year, Noguchi went to West Africa and worked doggedly to prove to himself that yellow fever was in fact a virus disease. Within six months he had confirmed this but just before his departure for New York he contracted yellow fever himself and died shortly after.