Yakushiji Kuninaga served as a bushō during the Sengoku period.  He was a senior retainer of the Hosokawa-Keichō family and served as the deputy military governor of Settsu Province.

Kuninaga was born as the eldest son of Yakushiji Motokazu.  In 1504, Motokazu was executed for launching a failed rebellion.  At this time, Kuninaga was still in his youth so avoided punishment.  In 1507, his lord, Hosokawa Masamoto, was assassinated in an event known as the Lord Hosokawa Incident.  Thereafter, Kuninaga became retainer of one of Masamoto’s adopted sons, Hosokawa Takakuni.  He then contributed to the elimination of his uncle, Yakushiji Nagatada, who participated in the plot to remove Masamoto.  As recognition for his achievements, in 1508, Kuninaga (known at the time as Mantokumaru), along with his younger brother Yakushiji Kunimori (known at the time as Iwachiyomaru), was appointed as the deputy military governor of Settsu.  In the twelfth month of 1509, he attended his coming-of-age ceremony and received one of the characters from the name of Takakuni, adopting the name of Kuninaga.  Thereafter, he maintained his affiliation with Takakuni, participating in numerous battles.  In 1527, Kuninaga was appointed as the lord of Yamazaki Castle in Yamashiro Province.  He then lost in battle against Hatanao Motokiyo who was acting in concert with Hosokawa Harumoto (the sucessor to Hosokawa Sumimoto and chief rival of Takakuni).  This caused him to flee to Takatsuki Castle in the Shimakami District of Settsu.  Subsequently, he surrendered to Harumoto.  Meanwhile, his younger brother, Kunimori, returned to the service of Takakuni and shared a common fate as Takakuni was defeated and killed during the Collapse at Daimotsu in 1531.

Later, Kuninaga served Harumoto and, in the first month of 1533, acquired support from followers of Hokke sect to fight against the Ikkō-ikki.  In the fifth month, upon orders of Harumoto, Kuninaga battled against Hosokawa Harukuni, the younger brother of Takakuni.  On 6/18, he died in battle in Takeo in Yamashiro Province.