This study explores the capability of Sulfate Radical-based Advanced Oxidation Processes (SR-AOPs) for the simultaneous disinfection and decontamination of urban wastewater. Sulfate and hydroxyl radicals in solution were generated activating peroxymonosulfate (PMS) under UV-C irradiation at pilot plant scale. The efficiency of the process was assessed toward the removal of three CECs (Trimethoprim (TMP), Sulfamethoxazole (SMX), and Diclofenac (DCF)) and three bacteria (Escherichia coli, Enterococcus spp., and Pseudomonas spp.) in actual urban wastewater (UWW), obtaining the optimal value of PMS at 0.5 mmol/L. Under such experimental conditions, bacterial concentration ≤ 10 CFU/100 mL was reached after 15 min of UV-C treatment (0.03 kJ/L of accumulative UV-C radiation) for natural occurring bacteria, no bacterial regrowth was observed after 24 and 48 h, and 80% removal of total CECs was achieved after 12 min (0.03 kJ/L), with a release of sulfate ions far from the limit established in wastewater discharge. Moreover, the inactivation of Ampicillin (AMP), Ciprofloxacin (CPX), and Trimethoprim (TMP) antibiotic-resistant bacteria (ARB) and reduction of target genes (ARGs) were successfully achieved. Finally, a harmful effect toward the receiving aquatic environment was not observed according to Aliivibrio fischeri toxicity tests, while a slightly toxic effect toward plant growth (phytotoxicity tests) was detected. As a conclusion, a cost analysis demonstrated that the process could be feasible and a promising alternative to successfully address wastewater reuse challenges.