Purpose There is a lack of real-world evidence of the comparative effectiveness of fidaxomicin versus vancomycin or metronidazole for treating patients with Clostridium difficile (CDI) infection. No systematic evidence comparing these treatment regimens using real-world observational studies was published up to date. The goal of this study is to compare the fidaxomicin and vancomycin/metronidazole regimens in terms of treatment outcomes in CDI patients. Methods Systematic and comprehensive search was carried out in the following databases and search engines: EMBASE, Cochrane, MEDLINE, ScienceDirect, and Google Scholar from 1954 until January 2022. Newcastle-Ottawa (NO) scale was used to assess the risk of bias. Meta-analysis was carried out using random effects model, and pooled odds ratios (OR) with 95% confidence interval (CI) were reported. Results A total of 10 studies satisfied the inclusion criteria, most of them were with poorer quality. The pooled OR was 0.40 (95% CI: 0.09-1.68; I-2 = 82.4%) for clinical cure and 2.02 (95% CI: 0.36-11.39; I-2 = 88.4%) for sustained cure. We reported pooled OR of 0.69 (95% CI: 0.40-1.20; I-2 = 65.7%) for the recurrence rate, 2.81 (95% CI: 1.08-7.29; I-2 = 70.6%) for the treatment failure, and 0.73 (95% CI: 0.50-1.07; I-2 = 0%) for all-cause mortality between patients that received fidaxomicin and vancomycin. The pooled OR was 0.71 (95% CI: 0.05-9.47; I-2 = 69.6%) in terms of recurrence between patients receiving fidaxomicin and metronidazole. Conclusion Fidaxomicin and vancomycin/metronidazole regimens did not have significant difference in terms of treatment outcomes, such as clinical cure, sustained cure, recurrence, and all-cause mortality. However, there was significantly higher risk of treatment failure in CDI patients taking fidaxomicin.