Born on March 13, 1815, in Milton, Pennsylvania. A graduate of Princeton University and the University of Pennsylvania School of Medicine. He once went to Qing China as a medical missionary but returned home because of his wife's health and had success as a doctor in New York. In 1859 he went to Japan as a missionary of the American Presbyterian Mission with his wife Clara and settled in Yokohama. Because Christianity was then still banned, he opened a clinic and treated patients without charge while waiting for an opening for evangelism. Outstanding also as a linguist, in 1867 he published Japan's first serious Japanese-English dictionary, the 'Waei Gorin Shusei.' The romanization he used for Japanese in that dictionary came to be called the 'Hepburn romanization' and became the foundation of modern romanized writing of Japanese. He also played a leading role in the Japanese translation of the New and Old Testaments (the Meiji translation of the Bible). The 'Hepburn School' he opened in 1863 became the source of Meiji Gakuin (today's Meiji Gakuin University). In 1892, after 33 years in Japan, he returned to the United States. He died in East Orange, New Jersey, in 1911 at the age of 95.

A rare all-round intellectual who combined physician, missionary, linguist, and educator. Humble and industrious, he never paraded his own name and devoted his life to the Japanese people. 'Medicine before evangelism' was his principle of practice, and tens of thousands of Japanese were saved by his free clinics. A devout Christian, he held deep respect for Japanese culture and poured his lifeblood into systematic research on kanji and the Japanese language.

Hepburn romanization continues to be used officially in modern Japanese passports, road signs, and international documents, and has become a bridge between Japanese and the world. The 'Waei Gorin Shusei' went through a third edition (1886) and is still studied as a classic of Japanese linguistics. Meiji Gakuin became the stronghold of the Yokohama Band — one of the three founts of Japanese Protestantism — and produced important figures of the Meiji literary world such as Shimazaki Toson. Through prewar and postwar, it has continued to uphold the tradition of Christian education.