Pharmaceutical residues in the aquatic environment are an emerging issue of global concern because of their effects on ecosystems including; antibacterial resistance development and endocrine disruption. Lake Victoria is the largest freshwater lake in Africa, and the second largest lake in the world. It is also the main source of the White Nile River, arguably the longest river in the world, flowing through South Sudan, Sudan, Ethiopia and Egypt, discharging into the Mediterranean Sea. However, its ecology is threatened by rapid industrialisation, urbanization, and increased agricultural activities, which have led to increased pollution via polluted runoffs. In this study, the occurrence of twenty-five pharmaceutical compounds (14 antibiotics, four anti-epileptic and antidepressant drugs, three analgesic and anti-inflammatory drugs, three beta-blockers, and one lipid regulator) was studied in 55 sediment samples obtained from the Ugandan sector of Lake Victoria, and their ecotoxic risk assessed. All the target compounds were quantifiable with levofloxacin (2–120 ng g−1 dm; dry mass), ciprofloxacin (3–130 ng g−1 dm) enoxacin (9–75 ng g−1 dm), ibuprofen (6–50 ng g−1 dm), metoprolol (1–92 ng g−1 dm) and propranolol (1–52 ng g−1 dm) being predominant. Murchison Bay, being the chief recipient of sewage effluents, municipal and industrial waste from Kampala city and its suburbs, had the highest levels. Ecotoxic risk assessment revealed that ciprofloxacin, levofloxacin, sulfamethoxazole, sulfamethazine, oxytetracycline, tetracycline, erythromycin, norfloxacin, ibuprofen, diclofenac, carbamazepine, atenolol, and metoprolol posed high toxic risks to sediment-dwelling organisms (risk quotients, RQ >1). This is the first study reporting concentrations and ecotoxic risks of pharmaceuticals in sediments of Lake Victoria, Uganda, and the whole of East Africa. Detection, identification and quantification of pharmaceuticals in Lake Victoria sediments is essential for gaining knowledge on their occurrence and fate which can ultimately be used to assist in constructing relevant policy and management recommendations.