Wastewater treatment plants (WWTPs) generate substantial amounts of sludge waste harboring antibiotic resistance genes (ARGs), posing significant environmental and public health risks. To mitigate these concerns, efficient technologies for sludge solubilization and simultaneous ARG decomposition are urgently required. This study aimed to optimize gamma irradiation conditions for enhanced sludge solubilization and simultaneous ARG decomposition. Using response surface methodology, we identified divergent optimal conditions for these two objectives. Maximum sludge solubilization was achieved at pH 11, 2.8 % total solids (TS), and an 18.2 kGy dose. In contrast, optimal ARG decomposition required different conditions of neutral pH 7, 7 % TS, and a 20 kGy dose. This operational trade-off is a central finding as conditions favoring solubilization resulted in lower ARG removal. While sludge solubilization increased linearly with dose, ARG decomposition exhibited a dose-dependent limitation, plateauing beyond 11.8 kGy. Decomposition efficiencies varied significantly across ARGs, ranging from 50 % (tetA) to > 75 % (tetQ, vanA, and sul1). ARG decomposition rates varied substantially among the different WWTPs. This suggests that factors such as microbial community structure, sludge characteristics, and biofilm properties critically influence decomposition efficiency. The findings reveal a critical need for tailored gamma irradiation strategies, carefully balancing operational conditions to simultaneously optimize sludge treatment efficiency and ARG mitigation in wastewater treatment contexts.