Otani Yoshitsugu is well known in Japan for two main aspects: his leprosy, and his friendship. Supposedly he was one who put friendship before anything (although obviously such a subjective matter is hard to determine), and it may have been in Korea that Ishida and Otani, working together, formed their legendary friendship. There is even an anecdote concerning this friendship, which goes something like this: A secret tea party was being held, and all those invited were passing around a cup of tea. As Otani Yoshitsugu took a sip, some pus from his face dropped into the cup. Yoshitsugu discovered this, but too late: the cup was already being passed around. The people who took sips after this all had horrified expressions on their faces, but when it came to Mitsunari's turn, he calmly drank all the remaining tea, pus and all. Yoshitsugu was amazed: "This Mitsunari is an extraordinary man!" [This story also is sometimes told in the same way, but with Hideyoshi drinking the tea.]

Before the battle of Sekigahara, Yoshitsugu was said to have repeatedly tried to persuade Mitsunari of the futility of his actions. However, at seeing the staunchness of his friend's convictions, Yoshitsugu joined his cause after mulling it over for several days. At the time, Yoshitsugu's health was deteriorating, making him nearly blind. He could not stand up, let alone fight. He was led to the battleground in a palanquin.

Yoshitsugu was at the head of about 600 men, with another 4000 or so under Toda Shigemasa, Hiratsuka Tamehiro, Otani Yoshikatsu (his son), and Kinoshita Yoritsugu (his nephew). As the battle raged on, Kobayakawa Hideaki, who was situated above Yoshitsugu on Mount Matsuo, didn't move, despite repeated calls from Ishida Mitsunari. Yoshitsugu suspected something, and thus called for his troops to position themselves so as to prepare for a possible attack from their flanks. His hunch was right, as following a stimulatory gun volley from Ieyasu's position, Kobayakawa Hideaki and his troops rushed down the mountain towards Yoshitsugu's position. This movement was immediately followed by Akaza Naoyasu, Ogawa Suketada, Kutsuki Mototsuna, and Wakizaka Yasuharu, a total of over 20000 troops.

Yoshitsugu's troops fought back, at one point even driving back Kobayakawa's troops partway up the mountain, but in the end, sheer numbers took their toll. While this was happening, Yoshitsugu, unable to see, repeatedly asked one of his retainers, Yuasa Goro, "Is it lost?" When the latter finally answered in the affirmative, Yoshitsugu asked him to cut his head off. He was 42.