Founded by Sasaki Yasutsuna of Ōmi province in the 13th century, the name Rokkaku was taken from their residence within Kyoto; however, many members of this family continued to be called Sasaki. Over the course of the Muromachi period, members of the clan held the high post of Constable (shugo) of various provinces.
During the Ōnin War (1467-77), which marked the beginning of the Sengoku period, the clan's Kannonji Castle came under assault. As a consequence of defeat in the field, the clan entered a period of decline.
Like other hard-pressed daimyos, the Rokakku tried to enhance their military position by giving closer attention to improved civil administration within their domain. For instance, in 1549, the Rokkaku eliminated a paper merchant's guild in Mino under penalty of confiscation. Then they declared a free market in its place.
The Rokakku were defeated by Oda Nobunaga in 1568 on his march to Kyoto and in 1570 they were absolutely defeated by Shibata Katsuie. During the Edo period, Rokkaku Yoshisuke's descendants were considered a kōke clan.