The Tijuana River Watershed is a vital ecosystem for a variety of species and humans that provides habitat and recreation. For hundreds of years, the Tijuana River Valley was inhabited by the Kumeyaay Native Americans, who managed the land through natural processes. As populations grew, the river valley faced various environmental and anthropogenic threats. Sewage pollution has been documented since the 1930s and is a well-known threat to the watershed and surrounding community. As human populations increase on both sides of the border, so does this issue. Biological oxygen demand (BOD) and dissolved oxygen (DO) are used as water quality indicators and can indicate high levels of pollutants. Spatial analyses of BOD revealed no spatial trends for the duration of this study. Longitudinal analyses of DO in the US–Tijuana River revealed weak downward trends in DO levels over time. Water temperature and precipitation data were gathered to evaluate the relationship with DO for the respective time scales to reveal potential environmental influences; however, none were statistically significant as to influence DO. Seasonality proved to have the greatest impact on DO in the US reaches of the Tijuana River and Estuary. Future climate projections hypothesize that global temperatures will continue to rise, and the San Diego region can expect more pronounced seasonality. The exacerbation of these extreme events could cause a greater change in annual DO between seasons and possibly more frequent environmental health issues.