Born in 1561 into the Ii family of Tōtōmi Province, he lost his father young and endured a difficult childhood. Around 1575 he began serving Tokugawa Ieyasu, whose recognition of his talents brought him unusually rapid advancement. He took over the red-armoured corps (akabisashi) of the former Takeda army and was known as "Red Ii." He took part in many battles including the Battle of Komaki and Nagakute (1584) and the Odawara Campaign (1590), and at the Battle of Sekigahara (1600) he served as the vanguard of the Eastern Army. He died in 1602 from a gunshot wound received at Sekigahara, aged 42. One of the Tokugawa Four Generals (alongside Honda Tadakatsu, Sakakibara Yasumasa, and Sakai Tadatsugu), he also played an important role as Ieyasu's diplomat. He became the first lord of the Hikone domain, and his descendants produced the late-Edo great elder Ii Naosuke.

Cool and composed yet bold and courageous on the battlefield. From a young age he also handled diplomacy and political negotiation as Ieyasu's close aide, showing high aptitude not only as a general but as a diplomat. The experience of overcoming childhood hardship led to a thoughtful consideration for his subordinates and a skill in winning people over. He also had a fine tactical eye that made maximum use of the visual intimidation of the red-armoured corps.

Rated especially highly among the Tokugawa Four Generals for his mobility and diplomatic skill, his vanguard performance at Sekigahara contributed to the victory of the Eastern Army. The Ii clan of the Hikone domain continued until the end of the Edo period, and the great elder Ii Naosuke felt deep reverence for Naomasa. The red-armoured battle dress is still preserved at Hikone Castle Museum and is celebrated as the finest armour of the Sengoku period.