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Dysbiosis of gut microbiota is well-described in patients with coronavirus 2019 (COVID-19), but the dynamics of antimicrobial resistance genes (ARGs) reservoir, known as resistome, is less known. Here, we performed longitudinal fecal metagenomic profiling of 142 patients with COVID-19, characterized the dynamics of resistome from diagnosis to 6 months after viral clearance, and reported the impact of antibiotics or probiotics on the ARGs reservoir. Antibiotic-naive patients with COVID-19 showed increased abundance and types, and higher prevalence of ARGs compared with non-COVID-19 controls at baseline. Expansion in resistome was mainly driven by tetracycline, vancomycin, and multidrug-resistant genes and persisted for at least 6 months after clearance of SARS-CoV-2. Patients with expanded resistome exhibited increased prevalence of Klebsiella sp. and post-acute COVID-19 syndrome. Antibiotic treatment resulted in further increased abundance of ARGs whilst oral probiotics (synbiotic formula, SIM01) significantly reduced the ARGs reservoir in the gut microbiota of COVID-19 patients during the acute infection and recovery phase. Collectively, these findings shed new insights on the dynamic of ARGs reservoir in COVID-19 patients and the potential role of microbiota-directed therapies in reducing the burden of accumulated ARGs.