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Decreases in clinical response of Clostridioides difficile to antibiotics used for its treatment have raised concerns regarding antibiotic resistance. We conducted a systematic review and meta-analysis to study the resistance rates of C. difficile to various antibiotics over time. We systematically searched MEDLINE, Embase, and Web of Science from inception through 03/31/2017 for observational studies assessing antibiotic resistance rates in C. difficile. Weighted summary estimates were calculated using inverse variance heterogeneity models [MetaXL software (v. 5.3)]. A priori subgroup analyses were done (by study year, continent, susceptibility testing method, origin of isolates); ribotype 027 strains were analyzed separately. From 1982 to 2017, 60 studies (8336 isolates) were analyzed. Fifty-three studies reported vancomycin resistance; weighted pooled resistance (WPR), 2.1% (95% CI, 0%–5.1%; I 2 = 95%). Fifty-five studies reported metronidazole resistance; WPR, 1.9% (95% CI, 0.5%–3.6%; I 2 = 89%). Compared to the period before 2012, vancomycin resistance increased by 3.6% (95% CI, 2.9%–4.2%; P < 0.001) after 2012, and metronidazole resistance decreased by 0.8% (95% CI, 0.1%–1.5%; P = 0.02). No isolates were resistant to fidaxomicin. Resistance of C. difficile to vancomycin is increasing, with a smaller, declining resistance to metronidazole; there is significant heterogeneity between studies. Ongoing monitoring of resistance to commonly used antibiotics is required. • Resistance of Clostridioides difficile to vancomycin has increased with time. • Resistance to metronidazole has decreased, though to a lesser extent. • Highest rates of resistance are from the Americas and Asia. • Resistance to fidaxomicin has not yet been reported. [ABSTRACT FROM AUTHOR]