The famed veteran of the invasion of Korea Shimazu Tadatsune called him the "Number one warrior in Japan" (日本一の兵).

[citation needed] In 1600, before the Battle of Sekigahara, Tokugawa Ieyasu rallied various daimyōs to attack Uesugi Kagekatsu.

The Sanada clan complied as well, but when Ishida Mitsunari decided to challenge Ieyasu, Masayuki and Yukimura joined the western forces, parting ways with Masayuki's eldest son and Yukimura's brother, Nobuyuki, who joined the eastern forces.

The true motive of Masayuki and Yukimura's decision is disputed with many theories, but there are two main schools of thought: in one, Masayuki made the decision (and Yukimura agreed); he expressed the willingness to take a gamble, so that if he were to join the weak side and win the battle, the Sanada would gain much more power.

The other theory is the opposite where they planned a safety net; Masayuki, Yukimura, and Nobuyuki discussed the situation when Ieyasu asked them to state their allegiance clearly, and they decided to join separate sides, so that, regardless of the outcome of the battle, the Sanada clan would survive.

However, as the castle did not fall in the short time that he expected, Hidetada gave up and joined the main Tokugawa army, too late however, to participate in the crucial Battle of Sekigahara.

The winter campaign began on November 19, 1614; Osaka Castle siege commenced on December 4, 1614, and lasted until January 22, 1615, when a truce was reached.

[citation needed] The Shōgun's forces were repeatedly repelled, and the Sanada troops launched a number of attacks against the siege lines, breaking through three times.

On June 3, 1615 (6th day of 5th month of 20 year of Keicho era), at the Battle of Dōmyōji, Sanada Yukimura was in command of the Osaka Army on the right wing and engaged in a battle with Date Masamune forces in the area of Emperor Ōjin's Tomb and Konda Hachiman Shrine.

This fight took place at around 12:00 and by 5:00 PM Sanada Yukimura made the decision to retreat towards Osaka Castle.

As the vanguard of the Tokugawa left flank under Matsudaira Tadanao marched to their positions, Yukimura's troops charged down from Chausuyama (茶臼山) and fought with desperate abandon together with Mori Katsunaga's contingent.

A myth says he indeed managed to kill Ieyasu, but the Ogoshō was replaced by a kagemusha (a decoy or doppelganger) called Ogasawara Hidemasa.

Another legend states that in the winter of 1614, Tokugawa Ieyasu sent an envoy to Yukimura with a notice that, if he were to abandon the Toyotomi cause, he would give him the entire prefecture of Shinano and 400,000 koku.