Born around 1559, likely in Omi Province, he served Hashiba Hideyoshi from youth and rose to a position rivaling the Five Commissioners, handling land survey administration, Korean campaign logistics, and other major duties in the Toyotomi government. At some point he developed a debilitating illness (possibly leprosy) and began covering his face with a white hood. The famous story of Ishida Mitsunari drinking from a tea bowl that everyone else had declined out of consideration for Yoshitsugu has become an enduring symbol of their friendship. On the eve of Sekigahara in 1600, Yoshitsugu warned Mitsunari repeatedly that the cause was hopeless. But when Mitsunari's resolve proved unshakeable, Yoshitsugu chose to stand by his friend's sense of honor and joined the Western army. At Sekigahara, he foresaw Kobayakawa Hideaki's betrayal and prepared countermeasures—but could not stop the cascade of defections that followed. Overwhelmed, he had his retainer Yuasa Gosuke assist his ritual suicide. He was approximately 41 years old.

Skilled in both arms and letters, he maintained dignity and cunning despite illness. His friendship with Mitsunari is symbolized by the tea-bowl anecdote—drinking what no one else dared touch.

Celebrated for sacrificing his life for friendship and honor. His Sekigahara camp site draws many admirers. He is revered as the embodiment of "gi" (righteousness) in the Sengoku era.