Wakisaka originally served under Akechi Mitsuhide, a vassal of Oda Nobunaga. In 1581, he was one of several who led Nobunaga's troops in the Siege of Hijiyama. The following year, Akechi betrayed Oda Nobunaga and took his power and lands, but was defeated two weeks later at the Battle of Yamazaki.
Wakisaka then joined the victor, Hashiba Hideyoshi, who had become a conspicuous figure as a retainer of Oda Nobunaga. Following the Battle of Shizugatake in 1583, Wakisaka came to be known as one of the shichi-hon-yari (七本槍), or Seven Spears of Shizugatake. These Seven would be among Hideyoshi's most trusted generals, especially in naval combat. Wakisaka was granted the fief of Awaji Island, worth 30,000 koku, in 1585. He was then made commander of part of Hideyoshi's fleet, taking part in Hideyoshi's 1587 campaigns in Kyūshū, the 1590 Siege of Odawara, and the invasions of Korea, which took place from 1592 to 1598.
During the disastrous invansion of Korea, Yasuharu met continuous defeat at the hands of Admiral Yi Sun-Sin and the Joseon Navy, most notably at the Battle of Hansando, where he lost his entire fleet and almost 10,000 soldiers. He met Admiral Yi again at many other battles including the Battle of Myeongnyang, where his force of 133 warships and 200 smaller ships was routed by Yi's fleet of 13 ships, and the Battle of Noryang. He lost all of his future encounters with Admiral Yi.
In 1600, Wakisaka was going to side with Tokugawa Ieyasu, but was compelled to oppose him, siding with Ishida Mitsunari, because Mitsunari raised Wakisaka's army when he stayed in Osaka. On October 21, sometime during the decisive battle of Sekigahara, Wakisaka switched sides along with Kobayakawa Hideaki. He defeated Otani Yoshitsugu's force, and contributed to the Tokugawa victory.
After the battle, Tokugawa allowed Wakisaka to continue governing his domain of Awaji.
In succeeding years, he was given another fief, at Ozu, Iyo Province, worth 53,000 koku.His son, Wakisaka Yasumoto, succeeded to the house after his death.