Antibiotic resistance has become a global public health problem. Recently, various environmental pollutants have been reported to induce the proliferation of antibiotic resistance. However, the impact of multiple pollutants (e.g., heavy metals and antibiotics), which more frequently occur in practical environments, is poorly understood. Herein, one widely distributed heavy metal (Ag+) and one frequently detected antibiotic (tetracycline) were chosen to investigate their coexisting effect on the proliferation of antibiotic resistance in the activated sludge system. Results show that the co-occurrence of Ag+ and tetracycline at environmentally relevant concentrations exhibited no distinct inhibition in reactor performances. However, they inhibited the respiratory activity by 42%, destroyed the membrane structure by 218%, and increased membrane permeability by 29% compared with the blank control bioreactor. Moreover, the relative abundances of target antibiotic resistance genes (ARGs) (e.g., tetA, blaTEM-1, and sulII) in effluent after exposure of coexisting Ag+ and tetracycline were increased by 92–1983% compared with those in control reactor, which were 1.1–4.3 folds higher than the sum of the sole ones. These were possibly attributed to the enrichments of antibiotic-resistant bacteria. The results would illumine the coexisting effect of heavy metals and antibiotics on the dissemination of ARGs in activated sludge system. Display omitted •Coexisting Ag+ and TC did not inhibit the bioreactor performance.•Coexisting Ag+ and TC caused more microbial damage.•Coexisting Ag+ and TC enriched ARGs in sludge and effluent.•Coexisting Ag+ and TC enriched heavy metal and antibiotic-resistant bacteria.