Antimicrobial resistance (AMR) plays an important role in the pathogenesis and spread of Clostridioides difficile infection (CDI). Many antimicrobials, such as fluoroquinolones, have been associated with outbreaks of CDI globally. This study characterized AMR among clinical C. difficile strains in Thailand, where antimicrobial use remains inadequately regulated. Stool samples were screened for tcdB and positives were cultured. C. difficile isolates were characterized by toxin profiling and PCR ribotyping. Antimicrobial susceptibility testing was performed by agar incorporation, and whole-genome sequencing and AMR genotyping were performed on a subset of strains. There were 321 C. difficile strains isolated from 326 stool samples. The most common toxigenic ribotype (RT) was RT 017 (18%), followed by RTs 014 (12%) and 020 (7%). Resistance to clindamycin, erythromycin, moxifloxacin, and rifaximin was common, especially among RT 017 strains. AMR genotyping revealed a strong correlation between resistance genotype and phenotype for moxifloxacin and rifaximin. The presence of erm-class genes was associated with high-level clindamycin and erythromycin resistance. Point substitutions in the penicillin-binding proteins were not sufficient to confer meropenem resistance, but a Y721S substitution in PBP3 was associated with a 4.37-fold increase in meropenem minimal inhibitory concentration. No resistance to metronidazole, vancomycin, or fidaxomicin was observed.