The root of the university was Yamaguchi Auditorium (山口講堂, Yamaguchi kōdō), a private school founded by Ueda Hōyō (上田鳳陽, 1769–1853) in 1815.

After the Meiji Restoration it became a prefectural secondary school, and in 1894 it developed into (older) Yamaguchi Higher School (山口高等学校, Yamaguchi kōtō gakkō), a national institute of higher education.

In February 1905 the school was reorganized into Yamaguchi Higher School of Commerce (山口高等商業学校, Yamaguchi kōtō shōgyō gakkō), the third national commercial college in Japan, after Tokyo (1887) and Kobe (1902).

In 1964 Yamaguchi Prefectural Medical College was merged into the university to constitute the School of Medicine.

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