Phenoxymethylpenicillin is a narrow-spectrum β-lactam antibiotic commonly used in South Africa. It is considered a pharmaceutical pollutant in municipal wastewater treatment plants (WWTPs), requiring wastewater-based epidemiology (WBE). Realistic simulation of phenoxymethylpenicillin degradation in wastewater treatment plants is limited by multifaceted microbial dynamics and fluctuating physicochemical conditions. This research examines pseudo-first-order degradation kinetics utilizing MATLAB calculations to estimate the distribution and transition pathways of phenoxymethylpenicillin in wastewater treatment plants in Johannesburg. Existing high-performance liquid chromatography–mass spectrometry (HPLC-MS) analytical data was used as modeling data, calibrated in line with critical parameters including sludge retention time (5–25 days), hydraulic retention times (4–12 hours), influent concentration variability (0.1-10 µg/L), degradation constant k (0.05–0.2 h^-1), and operating temperature profiles (15–30°C). Sensitivity analysis identified critical parameters influencing degradation, whereas model validation included the coefficient of determination (R²) and mean squared error (MSE) to compare simulated outputs with measured concentrations. The established model confirmed that pseudo-first-order kinetics effectively characterizes the degradation curve, exhibiting performance metrics of R² at 0.9734 and an MSE of 0.675, which are within acceptable thresholds, aligning with similar β-lactam research. The validated model provides dependable predictions of phenoxymethylpenicillin, facilitating the amalgamation of chemical kinetics, simulation modeling, and environmental engineering techniques to combat pharmaceutical contamination in urban water systems.