Pollutants introduced into urban streams through runoff and sewage contamination may significantly impair stream water quality and pose a serious threat to humans and wildlife. The biological and chemical indicators, E. coli, caffeine, and sucralose, were examined within Forester Creek to better understand the anthropogenic and wastewater influence within the stream. Forester Creek, a 10-mile tributary to the San Diego River, was chosen as the study site due to its previous wetland restoration project and its state of impairment for a variety of pollutants. Caffeine and sucralose were ubiquitously detected in Forester Creek with mean concentrations of 1.139 μg/L and 0.889 μg/L, respectively. The geometric mean E. coli density at all sampling sites exceeded the water quality criteria of 126 CFU/100 mL established by the U.S. EPA. Caffeine and sucralose displayed contrasting trends and patterns for all parameters studied in Forester Creek. Our results suggest that both chemical indicators of sewage contamination, caffeine and sucralose, as well as the biological indicator, E. coli, may all have different significant sources that contribute to their presence in Forester Creek. Weather can also significantly impact the levels of these indicators, but caffeine was the only indicator that showed a significant (p < 0.05) increase in levels in wet-weather as compared to dry-weather. Moreover, caffeine levels seemed to follow a first flush pattern with the highest levels observed on the rising portion of the hydrograph as compared to the remainder of the storm. The restored wetland segment displayed poor removal efficiencies for fecal indicator bacteria and the chemical tracers, caffeine and sucralose. The diversity of different sources for each of the biological and chemical indicators tested, as well as their differential behavior in wet-weather and persistence in the environment, suggest that even when used together, they are ambiguous indicators of contamination of raw sewage in Forester Creek.