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The presence of pharmaceuticals in the environment is undesirable since their biological activity may impair ecosystem health of reservoirs that receive inflows from other water sources. This work determined the concentrations of analgesics and antibiotics, and the occurrence of antimicrobial resistance among microbes in water and sediment samples from Owabi and Barekese reservoirs—two main sources of pipe-borne water in the Kumasi metropolis in Ghana. The study also assessed the knowledge, attitude, and practice of inhabitants near these reservoirs regarding the disposal of unused and expired medicines. Out of nine targeted pharmaceuticals, four were detected in at least one sample. Five analytes (caffeine, ciprofloxacin, doxycycline, ibuprofen, and metronidazole) were below detection limit for all samples. The levels of pharmaceuticals were low, as expected, ranging from 0.06 to 36.51 μg/L in the water samples and 3.34–4.80 μg/kg in sediments. The highest detected concentration of any pharmaceutical in water was for diclofenac (107.87 μg/L), followed by metronidazole (22.23 μg/L), amoxicillin (1.86 μg/L), chloramphenicol (0.85 μg/L), and paracetamol (0.16 μg/L). Chloramphenicol recorded the highest concentration (10.22 μg/kg) in the sediments. Five bacteria isolates (Enterobacter, Clostridium, Pseudomonas, Acinetobacter, and Klebsiella) from the samples were resistant to all the antibiotics tested. Isolates of Corynebacterium and Listeria showed susceptibility to only doxycycline. Isolates of Bacillus were susceptible to only two antibiotics (erythromycin and doxycycline). All the 100 respondents interviewed admitted that they dispose of medications once they do not need them. Of those who disposed of unwanted medicines, 79% did so inappropriately. Disposal in household trash (67%) was the most common method used. Majority of respondents felt the need for a facility or program to collect unused medicines (77%), hence their willingness to pay to reduce pollution by pharmaceuticals in the environment. It is quite clear from the ecotoxicological risk assessment that a single pharmaceutical at very low level as those in this study and other works is likely to pose many ecological risks upon long-term exposure and therefore cannot be ignored.