Musa-juku was one of the original staging points on the ancient Tōsandō highway connecting the capital of Heian-kyō with the provinces of eastern Japan from the end of the Nara period onwards.

During the Sengoku period, the nearby jōkamachi of Ōmihachiman was developed by Toyotomi Hidetsugu, and many traveling merchants (Ōmi shōnin (近江商人)) relocated to this area from the ruins of Azuchi Castle.

A road from Musa-juku extended towards Ise Province via Eigen-ji temple and the town of Yōkaichi, which was used by the Ōmi shōnin for transport of seafood, paper and cloth.

Musa-juku was on the sankin-kōtai route by the Kishū Tokugawa clan and other western daimyō en route to-and-from the Shogun's court in Edo; however, due to its proximity to the much-larger Otsu-juku and the fact that it was not on the marginally shorter Chōsenjin Kaidō (朝鮮人街道, "Korean Road") which ran closer to the shore of Lake Biwa, bypassing three stations of the Nakasendō including Musa-juku, meant that it attracted less traffic.

Per an 1843 the "中山道宿村大概帳" (Nakasendō Shukuson Taigaichō) guidebook issued by the Inspector of Highways (道中奉行, Dōchu-būgyō), the town had a population of 537 in 183 houses, including one honjin, one waki-honjin, and 23 hatago.