The oyster is one of the most abundantly harvested shellfish in the world. To explore the impact of salinity on antibiotic-resistant bacteria (ARB) and the microbial community associated with farmed oysters, oysters were taken from high-, medium-, and low-salinity zones (labeled HS, MS, and LS, respectively) in Qinzhou Bay of Beibu Gulf, China. ARB were tested with the Kirby–Bauer method. Species of ARB were confirmed by 16 S rDNA analysis. Microbial communities were analyzed by high-throughput sequencing technology. The results indicate that HS-derived ARB (>60%) resisted β-lactams and aminoglycosides and that LS-derived strains resisted macrolide and tetracyclines. All strains resisted 4 or more antibiotics. A total of 542 operational taxonomic units were detected in the samples, with Shewanella, Vibrio, and Endozoicomonas being the dominant genera (>80%), although distributed differently among the different salinity samples. The oyster microbial richness ranked as MS > LS > HS. This study provides an important reference for future efforts to explain factors or mechanisms underlying correlations between ARB, the microbiome, and salinity and thus the potential health of oysters in this region.