In 1872, after the abolition of the domains, the Mori family relocated to Tokyo. Mori stayed at the residence of Nishi Amane, in order to receive tutoring in the German language, which was the primary language for medical education at the time. In 1874, he was admitted to the government medical school (the predecessor for Tokyo Imperial University's Medical School), and graduated in 1881 at the age of 19, the youngest person ever to be awarded with a medical license in Japan. It was also during this time that he developed an interest in literature, reading extensively from the late-Edo period popular novels, and taking lessons in Chinese poetry and literature.
Mori was sent by the Army to study in Germany (Leipzig, Dresden, Munich, and Berlin) from 1884–1888. During this time, he also developed an interest in European literature. As a matter of trivia, Mori Ōgai is the first Japanese known to have ridden on the Orient Express.
Upon his return to Japan, he assumed a high rank as a medical doctor in the Japanese army and pushed for a more scientific approach to medical research, even publishing a medical journal out of his own funds.
Meanwhile, he also attempted to revitalize modern Japanese literature and published his own literary journal (Shigarami sōshi, 1889–1894) and his own book of poetry (Omokage, 1889). In his writings, he was an “anti-realist”, asserting that literature should reflect the emotional and spiritual domain. Maihime (舞姫, The Dancing Girl, 1890) described an affair between a Japanese man and a German woman.
In 1899, he married Akamatsu Toshiko, daughter of Admiral Akamatsu Noriyoshi, a close friend of Nishi Amane. He divorced her the following year under acrimonious circumstances that irreparably ended his friendship with Nishi.
During the Russo-Japanese War of 1904–1905, he was again sent to Manchuria. He later came under criticism for his stubborn refusal to believe that beriberi was not an infectious disease but an ailment caused by thiamine deficiency, despite evidence presented by Takaki Kanehiro of the Imperial Japanese Navy. His questionable decisions led to the death of 27,000 Japanese soldiers to beriberi, compared to 47,000 deaths from combat.
In 1907, Mori was promoted to Army Surgeon-General, the highest post within the Japanese medical corps. On his retirement in 1916 he was appointed director of the Imperial Museum.
His later works can be divided into three separate periods. From 1909–1912, he wrote mostly fiction based on his own experiences. This period includes Vita Sexualis, and his most popular novel, Gan (1911–13; The Wild Geese), which is set in 1881 Tokyo and was filmed by Shiro Toyoda in 1953 as The Mistress.
From 1912–1916, he wrote mostly historical stories. Deeply affected by the seppuku of General Nogi Maresuke in 1912, he explored the impulses of self-destruction, self–sacrifice and patriotic sentiment. This period includes Sanshō Dayū (山椒大夫), and Takasebune (高瀬舟).
From 1916, he turned his attention to biographies of late Edo period doctors.
A house which Mori lived in is preserved in Kokura Kita ward in Kitakyushu, not far from Kokura station. Here he wrote Kokura Nikki (Kokura diary). His birthhouse is also preserved in Tsuwano. The two one-story houses are remarkably similar in size and in their traditional Japanese style.