Prehistoric resource depression has been widely documented in many late Holocene contexts characterized by expanding human population densities, and has been causally linked to a wide range of other significant changes in human behavior and biology. Some of the more detailed records of this phenomenon have been derived from the San Francisco Bay area of California, including a possible case of anthropogenic sturgeon depression, but evidence for the latter was derived from limited fish-bone samples. We synthesize and analyze a massive ichthyoarchaeological data set here, including over 83,000 identified fish specimens from 30 site components in the central San Francisco Bay, to further test this hypothesis. Allometric live weight relationships from selected elements are established to reconstruct size change in white sturgeon (Acipenser transmontanus) through time, and—collectively—the data show significant linear declines over the last 3,000 years in the relative abundance of sturgeon compared to all other identified fishes, as well as declines in the maximum and mean weights of the harvested fish. Both these patterns are consistent with resource depression and do not appear to be related to changes in the estuarine paleoenvironment. Variation in sturgeon abundances also declines through time, in a pattern that reflects the single local source of this resource. These data have implications for both late Holocene regional human settlement systems and modern management of sturgeon populations, which are among the most imperiled animal populations on earth.