The presence of antibiotics in water and wastewater is a serious environmental concern of emerging interest globally. Their effective removal with a single treatment process is, however, challenging because of their widely varying characteristics, and requires innovative integration of treatment processes. In this study, sonophotocatalytic oxidation process was integrated with an aerobic sequencing batch reactor (SBR) for the comprehensive removal of a mixture of antibiotics. Initially, a Central Composite Design using Response Surface Methodology was used to optimise the operational parameters, viz. ultrasound (US) frequency, pH, and catalyst dosage, for the removal of Ciprofloxacin (CPX), Amoxicillin (AMX), and Tetracycline (TTC) in simulated wastewater. An optimised condition of 20 kHz US frequency, 6.59 initial pH, and 0.94 g L−1 catalyst dosage was observed for the maximum pollutant removal. These experimental conditions were subsequently used for combined sonophotocatalysis-aerobic SBR treatment. Three SBR systems representing a control system, pre-treated system, and untreated system, were used for the study. All three systems were able to achieve an average COD and NH4+-N removal of 85 % and 98 %, respectively. Results from the biological systems concluded that an enhanced CPX and TTC removal was observed in the pre-treated system, whereas maximum AMX removal was observed in the untreated SBR system. The metagenomic analysis confirmed the significant difference of microbial species with the addition of pretreated and untreated wastewater into the biological reactor, and pretreated system having higher number of species and greater biodiversity in comparison to untreated system.