After his father, Amago Masahisa, died early in battle, he became the head of Amago clan in 1537 after his grandfather stepped down. He launched a series of invasions to expand his domain, going as far as Harima. But in 1540, the Siege of Koriyama against Mōri Motonari ended in a humiliating defeat, and many of his retainers defected believing that Haruhisa's days were numbered. His grandfather Amago Tsunehisa died the next year and Ōuchi Yoshitaka launched a counter attack to finish the Amago clan. Haruhisa managed to stave off the invasion, encouraging those retainers who had defected earlier, and after gathering enough troops, managed to repel it. From this point, Haruhisa worked to secure his footing and control of such domains as Izumo, Hoki, Mimasaka, and Oki. When on 1551, Ōuchi Yoshitaka was killed by Sue Harukata's rebellion, in 1552, the Muromachi shogunate offered Haruhisa lordship over eight domains including those four domains he already fully controlled.

In his later years, Haruhisa suddenly decided to kill his uncle Amago Kunihisa as well as those retainers under him collectively called Shingūtō (新宮党) from the town Shingū which was their power base, resulting in a serious shortage of battle proven leaders. While it was generally thought, largely from various fiction works that emphasize Mori Motonari's prowess, that this action was carried out by Motonari in order to weaken Haruhisa's power, it is now thought most likely that this was a move by Haruhisa himself to solidify control of the Amago clan.

When Sue Harutaka lost against Mori Motonari dying in the Battle of Itsukushima, Haruhisa saw an opportunity to claim Iwami and making an alliance with Ogasawara clan of Iwami, moved to claim Omori Silver Mine. Motonari launched a counter attack and both clashed in a string of battles with no clear winner. Haruhisa collapsed in Gassantoda Castle on 1560 while engaged in a battle against Motonari and died on January 9.

It is written in Unyo Gunjitsuki that Amago Hisayuki commented that Haruhisa is Quick to act lacking in the discipline of a general, quick to seek battle lacking in the forgiveness.