The presence of antibiotics in wastewater poses significant threat to our ecosystems and health. Traditional biological wastewater treatment technologies have several limitations in treating antibiotic-contaminated wastewaters, such as low removal efficiency and poor process resilience. Here, a novel electrochemical-coupled sulfur-mediated biological system was developed for treating wastewater co-contaminated with several antibiotics (e.g., ciprofloxacin (CIP), sulfamethoxazole (SMX), chloramphenicol (CAP)). Superior removal of CIP, SMX, and CAP with efficiencies ranging from 40.6 ± 2.6 % to 98.4 ± 1.6 % was achieved at high concentrations of 1000 μg/L in the electrochemical-coupled sulfur-mediated biological system, whereas the efficiencies ranged from 30.4 ± 2.3 % to 98.2 ± 1.4 % in the control system (without electrochemical stimulation). The biodegradation rates of CIP, SMX, and CAP increased by 1.5∼1.9-folds under electrochemical stimulation compared to the control. The insights into the role of electrochemical stimulation for multiple antibiotics biodegradation enhancement was elucidated through a combination of metagenomic and electrochemical analyses. Results showed that sustained electrochemical stimulation significantly enriched the sulfate-reducing and electroactive bacteria (e.g., Desulfobulbus, Longilinea, and Lentimicrobiumin on biocathode and Geobactor on bioanode), and boosted the secretion of electron transport mediators (e.g., cytochrome c and extracellular polymeric substances), which facilitated the microbial extracellular electron transfer processes and subsequent antibiotics removal in the sulfur-mediated biological system. Furthermore, under electrochemical stimulation, functional genes associated with sulfur and carbon metabolism and electron transfer were more abundant, and the microbial metabolic processes were enhanced, contributing to antibiotics biodegradation. Our study for the first time demonstrated that the synergistic effects of electrochemical-coupled sulfur-mediated biological system was capable of overcoming the limitations of conventional biological treatment processes. This study shed light on the mechanism of enhanced antibiotics biodegradation via electrochemical stimulation, which could be employed in sulfur-mediated bioprocess for treating antibiotic-contaminated wastewaters.