Antimicrobial resistance (AMR) plays an important role in the spread and pathogenesis of Clostridioides difficile infection (CDI). An association between AMR and outbreaks of CDI has been identified, however, such studies have been limited to a few strain types in limited geographical regions. This study aimed to investigate the prevalence of AMR genotypes in the global population of C. difficile. Utilising the database at the National Center of Biotechnology Information (NCBI), 10,330 non-clonal C. difficile genomes were characterised by multi-locus sequence typing and AMR genotyping using SRST2-based approach. C. difficile genomes were grouped into one of 8 known evolutionary clades (clades 1 – 5 and cryptic clades I-III). A total of 4,532 C. difficile genomes (44%) in 89 sequence types (STs) across clades 1 – 5 were genotypically resistant to at least one antimicrobial, with 901 genomes (9%) being resistant to three or more antimicrobial classes, i.e. multidrug-resistant (MDR). No AMR genotype was identified in the cryptic clades. AMR prevalence was higher in clades 2 (84%), 4 (82%) and 5 (65%) compared to other clades (collectively 27%, p<0.0001). MDR prevalence was highest in clade 4 (62%) which was over three times higher than in clade 2, the clade with second-highest MDR prevalence (18%). There was a strong association between specific AMR and three major epidemic C. difficile STs: ST1 (clade 2) with fluoroquinolone resistance (mainly T82I substitution in GyrA, p<0.0001), ST11 (clade 5) with tetracycline resistance (various tet-family genes, p<0.0001), and ST37 (clade 4) with macrolide-lincosamide-streptogramin B (MLSB) resistance (mainly ermB gene, p<0.0001) and MDR (p<0.0001), highlighting the role of AMR in C. difficile outbreaks. Despite being intrinsically resistant to aminoglycosides, 12% of C. difficile carried accessory aminoglycoside resistance determinants, denoting an AMR reservoir role for C. difficile. In conclusion, this study provides a species-wide prevalence of AMR in C. difficile.