Yōsuke Matsuoka became a director of the South Manchurian Railway Company in 1922. In 1927, Matsuoka was promoted to the position of Vice-President of the South Manchurian Railway Company. He was also responsible for the expansion of the coal mines in Fushun and the construction of a coal liquefaction plant. However, in 1930, he resigned from the South Manchurian Railway and returned to Japan. In the 1930 General Election, Matsuoka ran for a seat in the Lower House of the Diet of Japan from Yamaguchi Prefecture with the support of the Rikken Seiyūkai (Constitutional Association of Political Friendship) political party.
However, following the Manchurian Incident of 1931, the establishment of Manchukuo and the Lytton Report to the League of Nations condemning Japan's actions, Matsuoka was drawn back into the arena of foreign affairs to head Japan's delegation to the League of Nations in 1933. Matsuoka gained international notoriety for a speech condemning the League of Nations and announcing Japan's withdrawal, leading the Japanese delegation out of the League's assembly hall.
Following his return to Japan, Matsuoka announced his resignation from the Rikken Seiyūkai and his intent to form his own political party modeled after the National Fascist Party in Italy. However, the party never gained the mass support Matsuoka had anticipated, and in 1935 he returned to Manchuria as president of the South Manchuria Railway. He held that post until 1939. Despite his admiration of the Italian fascist movement, Matsuoka was also a supporter of the plan to settle Jewish refugees in Manchukuo.
Yosuke Matsuoka delivering a speech "Dissolution of Political Parties" on March 17, 1934.