Pesticides are widely used for safeguarding agricultural yields and controlling malaria vectors, yet are simultaneously unintentionally introduced in aquatic environments. To assess the severity of this pressure in the Lake Tana Basin (Ethiopia), we evaluated the occurrence of 17 pesticide residues in the lake, tributary rivers, and associated wetlands during the wet and dry season, followed by a questionnaire. These questionnaires indicated that 35 different compounds were available in the districts surrounding the lake, including pesticides that are banned in Europe, i.e., endosulfan, dicofol, and malathion. Nevertheless, only 7 pesticide residues were detected in the assessed aquatic habitats. Of these, DDE and bifenthrin occurred most often (97.7% and 62.3%, respectively), while alachlor displayed the highest mean concentration (594 ± 468 ng/L). No significant differences were observed in residue concentrations between seasons nor between habitats. Based on an ecotoxicological risk assessment, the observed concentrations of DDE and cypermethrin pose a high risk to aquatic life, while alachlor and DDT-op residues were below the threshold values. Furthermore, a human risk assessment indicated a low risk for the population that directly consumes water from the Tana basin, while acknowledging the potential of indirect exposure through the consumption of fish and locally grown crops.