O Se-chang was born into the jungin class as the eldest son of O Gyeong-seok (오경석; 吳慶錫, 1831–1879), interpreter (역관; 譯官) of Chinese and collector of calligraphy and paintings.
At the age of 16, O Se-chang passed the civil service examination in Chinese (한학; 漢學) translation and interpretation (역과; 譯科).
Due to his close association with members of the Reform Party such as Kim Ok-gyun, Park Yeong-hyo, and Yu Gil-jun, he was arrested for the involvement in the 1884 Gapsin Coup, but was released without charges.
In 1897, he taught the Korean language for a year at the Tokyo College of Commerce (東京商業學校) at the invitation of the Japanese Ministry of Education.
As an avid collector of paintings and calligraphy, as well as a talented painter-calligrapher himself, he co-founded the first modern artists' association, Seohwa Hyeophoe (서화협회, 書畵協會, Calligraphy and Painting Association) with celebrated artists such as An Jung-sik (안중식, 安中植, 1861–1919), Jo Seok-jin (조석진, 趙錫晋, 1853–1920), and Kim Gyu-jin (김규진, 金奎鎭, 1868–1933) in 1918.