Low-oxygen and low-pH events are an increasing concern and threat in the Eastern Pacific coastal waters, and can be lethal for benthic and demersal organisms on the continental shelf. The normal seasonal cycle includes uplifting of isopycnals during upwelling in spring, which brings low-oxygen and low-pH water onto the shelf. Five years of continuous observations of subsurface dissolved oxygen off Southern California, reveal large additional oxygen deficiencies relative to the seasonal cycle during the latest La Niña event. While some changes in oxygen related to the isopycnal depression/uplifting during El Niño/La Niña are not unexpected, the observed oxygen changes are 2–3 times larger than what can be explained by cross-shore exchanges. In late summer 2010, oxygen levels at mid-depth of the water column reached values of 2.5 ml/L, which is much lower than normal oxygen levels at this time of the seasons, 4–5 ml/L. The extra uplifting of isopycnals related to the La Niña event can explain oxygen reductions only to roughly 3.5 ml/L. We find that the additional oxygen decrease beyond that is strongly correlated with decreased subsurface primary production and strengthened poleward flows by the California Undercurrent. The combined actions of these three processes created a La Niña-caused oxygen decrease as large and as long as the normal seasonal minimum during upwelling period in spring, but later in the year. With a different timing of a La Niña, the seasonal oxygen minimum and the La Niña anomaly could overlap to potentially create hypoxic events of previously not observed magnitudes.