A promising hierarchical nanocomposite of MIL-53(Al)/ZnO was synthesized as a visible-light-driven photocatalyst to investigate the degradation of amoxicillin (AMX). MIL-53(Al)/ZnO ultrafine nanoparticles were obtained by preparing Zn-free MIL-53Al and employing it as a reactive template under hydrothermal and chemical conditions. The synthesized nanocomposite (MIL-53(Al)/ZnO) has a low content of Al > 1.5% with significantly different characterizations of the parent compounds elucidated by various analyses such as SEM, TEM, XRD, EDX, and UV–Vis. The effect of operational parameters (catalyst dose (0.2–1.0 g/L), solution pH (3–11), and initial AMX concentration (10–90 mg/L)) on the AMX removal efficiency was studied and optimized by the response surface methodology. A reasonable goodness-of-fit between the expected and experimental values was confirmed with correlation coefficient (R2) equal to 0.96. Under the optimal values, i.e., initial AMX concentration = 10 mg/L, solution pH ~ 4.5, and catalyst dose = 1.0 g/L, 100% AMX removal was achieved after reaction time = 60 min. The degradation mechanism and oxidation pathway were vigorously examined. The AMX degradation ratios slightly decreased after five consecutive cycles (from 78.19 to 62.05%), revealing the high reusability of MIL-53(Al)/ZnO. The AMX removal ratio was improved with enhancers in order ($${\mathrm{IO}}_{4}^{-}$$
IO
4
-
> H2O2 > S2O8−2). The results proved that 94.12 and 98.23% reduction of COD were obtained after 60 and 75 min, respectively. The amortization and operating costs were estimated at 3.3 $/m3 for a large-scale photocatalytic system.