In 1522, he fought the Amago clan along with his father, Yoshioki, to win the control of Aki Province. Upon Yoshioki's death in 1528, Yoshitaka became the head of Ōuchi clan. In the 1530s, he led a military actions in the northern Kyūshū, defeating Shōni clan to win control of the area. With his back then secure, in 1540 he again started combating the Amago clan and by 1541, managed to completely control the Aki province.

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. His 1542–43 Siege of Toda Castle ended in failure. He completely lost his ambitions of expanding his domains and devoted his energy to the arts and culture. His retainers split into two factions. Those led by Sagara Taketō wanted the Ōuchi clan to simply do nothing more than maintain the control of their current domains, while those led by Sue Harukata wanted to continue expanding. Yoshitaka sided with the former.

Under the patronage of Yoshitaka, foreign trade and the arts flourished, and the Ōuchi home city Yamaguchi prospered greatly. In addition, Yoshitaka also attracted the Portuguese missionary Francis Xavier, and allowed him to proselytize while he was in Yamaguchi. At the same time, Yoshitaka fostered a close relationship with Emperor Go-Nara in Kyoto, and sponsored many imperial rites that the imperial court could not have afforded otherwise. On March 27, 1551, the embattled emperor appointed Ōuchi Yoshitaka as Acting Governor of Yamashiro (山城権守), the home province where the imperial capital Kyoto was located, in a bid to leverage the Ōuchi against the ravages of the warlord Miyoshi Nagayoshi, who occupied the capital. Yoshitaka, as Acting Governor of Yamashiro and, by extension, the protector of the court, embarked on a daring plan to relocate the emperor and the court to Yamaguchi. 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). By the end of the eighth month of 1551, nearly the whole court, save for the emperor himself and the palace ladies, was in Yamaguchi.

The military establishment of the Ōuchi resented Yoshitaka's apparent "weakness" and his plan to settle the imperial court in Yamaguchi — such a move would see privileges accorded to the courtiers and undermine their own standing within the Ōuchi clan. In September 1551, the faction led by Sue Harukata revolted and attempted to take over the Ōuchi clan. 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 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.　

大內義隆為大內義興的嫡長男；1522年與1524年曾經隨父出陣；1525年以後，原屬尼子氏的毛利元就依附於大內。1528年父親死後，繼任大內家家督。

大內義隆就任之後，開始進攻北九州；與大友義鎮、少貳資元發生戰爭，支配松浦氏、滅亡少貳家，完成北九州沿岸的經略。

1536年，大內義隆從朝廷得到大宰大貳的官位。1537年，受將軍足利義晴邀請，嘗試進軍京都。惟行經尼子氏的領地時，連連失利。1540年，尼子詮久入侵安藝(吉田郡山城之戰)，義隆派兵反擊，完全平定安藝境內，並攻下出雲國白鹿城等城。1542年，開始攻擊尼子氏主城－月山富田城，為尼子晴久所擊敗(第一次月山富田城之戰)，當時大內義隆的養子大內晴持也戰死。

從此大內義隆停止擴張領地，重用以相良武任為首的文治派以經營領地，並且倡導特有的大內文化（包括天主教和眾道），可見大內義隆是一位注重文化與貿易的大名。本身也對和歌與連歌等京都文化事物表達很強的關心，並且與文化人有所來往。在獨占與明朝和朝鮮王朝的勘合貿易的同時，將朝鮮的大藏經於日本出版，同時允許基督教的沙勿略於山口傳教。但如此則與陶隆房、內藤興盛等希冀持續以武力擴張勢力的武斷派對立起來。

1551年，屬下陶晴賢發動叛亂，大內義隆被迫於長門的大寧寺自殺(大寧寺之變)，享年四十五歲；大內家由權臣陶晴賢從大友家接來做義隆養子的大友晴英（即大內義長）接任家督，日明勘合貿易斷絕。

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