Two simple, rapid, low-cost, and provident chromatographic approaches were introduced and certified for the quantitative estimation of ciprofloxacin, indomethacin, and metronidazole residues in production wastewater samples. Preparation of the samples was made using a solid-phase extraction technique, and before analysis, it was carried out on bond Elut C18 packs. The first technique was TLC densitometric determination at 278 nm. The separation was carried out on TLC (Thin Layer Chromatography) plates (silica gel 60 F254) as a stationary phase and ethyl acetate: methanol: dichloromethane: n-hexane: ammonia (33%) (3.6: 3: 6: 2: 1, by volume) as a mobile phase. The second method was high-performance liquid chromatography (HPLC). The separation has been accomplished on Equisil BDS C18 column and UV (Ultra Violet) detection at 278 nm. Acetonitrile/phosphate buffer mixture of pH 3 (75:25; v/v) is the mobile phase, the pH was adjusted using o-phosphoric acid, which is adapted to a flow rate of 1.5 mL/min. The previously stated techniques have been confirmed according to ICH guidelines. The methods described were used to accurately assess the drug residues studied in laboratory-prepared mixtures and actual industrial waste-water samples to confirm that it is free from these drug residues so it can be recycled and used for irrigation and other purposes.