Severe outbreaks and deaths have been linked to the emergence and global spread of fluoroquinolone-resistantClostridioides difficileover the past two decades. At the same time, metronidazole, a nitro-containing antibiotic, has shown decreasing clinical efficacy in treatingC. difficileinfection (CDI). Most metronidazole-resistantC. difficileexhibit an unusual resistance phenotype that can only be detected in susceptibility tests using molecularly intact heme. Here, we describe the mechanism underlying this trait. We find that most metronidazole-resistantC. difficilestrains carry a T-to-G mutation (which we term PnimBG) in the promoter of genenimB, resulting in constitutive transcription. Silencing or deletingnimBeliminates metronidazole resistance. NimB is related to Nim proteins that are known to confer resistance to nitroimidazoles. We show that NimB is a heme-dependent flavin enzyme that degrades nitroimidazoles to amines lacking antimicrobial activity. Furthermore, occurrence of the PnimBGmutation is associated with a Thr82Ile substitution in DNA gyrase that confers fluoroquinolone resistance in epidemic strains. Our findings suggest that the pandemic of fluoroquinolone-resistantC. difficileoccurring over the past few decades has also been characterized by widespread resistance to metronidazole.