Pharmaceuticals such as ibuprofen, paracetamol, and caffeine are commonly found in wastewater due to incomplete removal in conventional treatment systems. This study evaluated three vertical constructed wetland (V-CW) configurations: V1 (gravel–sand with vegetation), V2 (biochar–zeolite with vegetation), and V3 (biochar–zeolite without vegetation). All systems achieved high removal efficiencies for organic matter (Chemical Oxygen Demand (COD): 89.4–91.7%, Biochemical Oxygen Demand over 5 days (BOD₅): 93.3–93.8%, Total Suspended Solids (TSS): 94.5–96.6%) and pharmaceuticals (ibuprofen: 81.8–91.5%, paracetamol: 90.0–94.3%, caffeine: 93.1–97.2%). Statistical analysis showed that substrate type significantly influenced ibuprofen (p = 0.0035) and caffeine (p = 0.0436) removal, while vegetation had no significant effect (p > 0.266). The enhanced performance of biochar and zeolite can be attributed to their high adsorption capacity and microbial support, with adsorption and biodegradation identified as dominant removal mechanisms, as reported in previous research. These findings highlight the importance of engineered substrates in optimizing constructed wetlands for wastewater treatment to improve the removal of emerging contaminants. Future research should focus on long-term substrate performance, cost-effectiveness, and field-scale validation, particularly in regions with vulnerable groundwater systems such as the Yucatán Peninsula.