Modern chemistry has produced many compounds that facilitate everyday life and improve health. Accumulation of synthetic chemicals in the natural environment is a measurable byproduct of these advances. These chemicals of emerging concern (CECs) include pharmaceuticals, fragrances, detergents, disinfectants, plasticizers, preservatives, and many others, and are ubiquitous in wastewater and agricultural and urban runoff. Many reconnaissance efforts in recent years have assessed the presence of CECs in water and sediment, but geographic coverage remains limited. The Columbia River is the fourth largest river by volume in the United States, and provides important hydroelectric power generation, anadromous fisheries, large recreational areas, scenic beauty, and valuable habitat for wildlife and fish. The Columbia River estuary, at the convergence of the Columbia River and Pacific Ocean, is one of the most biologically productive ecosystems in the world due to its rich nutrient profile. Despite its importance to threatened and endangered anadromous fish, and its documented CEC inputs, the estuary has rarely been sampled for these compounds. In this study, we sampled water and suspended solids at several locations within the estuary, and tested for a large suite of pharmaceuticals, personal care products, antibiotics, industrial compounds, and others. We compare results of sampling conducted in 2004 and in 2014, and during different seasons. We observed seasonal and temporal differences in detection patterns, and, despite extensive dilution in this large river, we found multiple compounds from each of the chemical classes tested. This effort confirms the presence of CECs in the estuary and the need for additional studies to understand routes of exposure, bioaccumulation pathways, and effects of these compounds on aquatic organisms and food web.