Ueda Castle was the site of two battles between the Sanada and the Tokugawa clan, notably the Siege of Ueda in 1600 when Sanada Masayuki with a force of 2000 men held off Tokugawa Hidetada's invading force of 38,000 men for so long that they arrived late for then Battle of Sekigahara.
Following the establishment of the Tokugawa shogunate, Sanada Nobuyuki was confirmed as daimyō with Ueda Domain, with holdings assessed at 95,000 koku.
However, Tadamasa died in 1628 before his plans to rebuild Ueda castle were realised, and his son Sengoku Tadatoshi became embroiled in a dispute over land surveys.
Matsudaira Tadachika served in many important roles within the administration of Tokugawa Ieshige, including Kyoto shoshidai from 1717 through 1724 and rōjū in 1724, His son, Matsudaira Tadazane, gave 5000 koku to his younger brother, reducing the domain to 53,000 koku.
Under the new Meiji government, Matsudaira Tadanari, the last daimyo of Ueda Domain went to study at Rutgers University and was given the kazoku peerage title of shishaku (viscount).