In the 1530s, he led military actions in the northern Kyūshū, defeating Shōni clan to win control of the area.

However, in 1542, an invasion into Izumo Province ended in a disaster, with Yoshitaka losing his adopted son Ōuchi Harumochi along with large number of troops against Amago Haruhisa.

Under the patronage of Yoshitaka, foreign trade and the arts flourished, and the Ōuchi home city Yamaguchi prospered greatly.

High-ranking courtiers and performers of imperial rites moved to Yamaguchi, including dignitaries such as former regent (kampaku) Nijō Tadafusa and retired Grand Minister (Sadaijin) Sanjō Kin'yori (三条公頼; father-in-law of Takeda Shingen).

With the control of troops in Harukata's hand, it was over in few days—the courtiers and ministers were massacred and Yoshitaka was forced to perform seppuku at the Tainei-ji Temple (大寧寺) in Nagato Province[5][6] after composing his death poem: Both the victor and the vanquished are but drops of dew, but bolts of lightning – thus should we view the world.