The San Mateo County Historical Association was founded in 1935. One of its early champions was Dr. Frank Stanger, a history professor at San Mateo Junior College, now the College of San Mateo. Through Stanger's efforts, the museum was founded in a college classroom in 1963. For 35 years, it operated from that academic setting before moving to its current home, the former courthouse, which opened as a museum on February 6, 1999. The move gave the museum the kind of space its collections deserved: approximately 420,000 items spanning two and three dimensions, from photographs and documents to tools and artifacts of Peninsula life.

The permanent exhibitions weave together the strands of San Mateo County's identity. Nature's Bounty explores how the early people of the Peninsula used natural resources to support daily life and build San Francisco. Journey to Work traces how transportation transformed the county from frontier to suburb. Living the California Dream uses an object theater with lighting effects and video projection to trace the evolution of suburban life through artifacts. A 1999 exhibition about San Mateo County's grizzly bear history remains one of the museum's most memorable installations, reminding visitors that the state animal once roamed the same hills that now hold tract homes and shopping centers.

The Historical Association also operates two historic sites that extend the museum's story into the landscape. The Woodside Store, one of the earliest commercial buildings on the Peninsula, tells the story of frontier trade. The Sanchez Adobe, completed in 1846 by Francisco Sanchez, one-time alcalde of Yerba Buena, sits on a site of even deeper significance. During Native California times, the Aramai people established the village of Pruristac there. During the Spanish colonial period, it served as an agricultural outpost. Extensive archaeological investigations since 1978 have revealed layers of habitation stretching back centuries. In 2016, the association conducted school programs for nearly 20,000 children across its three locations.