We use hydrographic data from the California Cooperative Oceanic Fisheries Investigations program to explore the spatial and temporal variability of dissolved oxygen (DO) in the southern California Current System (CCS) over the period 1984–2006. Large declines in DO (up to 2.1 μmol/kg/y) have been observed throughout the domain, with the largest relative DO declines occurring below the thermocline (mean decrease of 21% at 300 m). Linear trends were significant (p < 0.05) at the majority of stations down to 500 m. The hypoxic boundary (∼60 μmol/kg) has shoaled by up to 90 m within portions of the southern CCS. The observed trends are consistent with advection of low-DO waters into the region, as well as decreased vertical oxygen transport following near-surface warming and increased stratification. Expansion of the oxygen minimum layer could lead to cascading effects on benthic and pelagic ecosystems, including habitat compression and community reorganization.