In the human gut, the growth of the pathogenClostridioides difficileis impacted by a complex web of interspecies interactions with members of human gut microbiota. We investigate the contribution of interspecies interactions on the antibiotic response ofC.difficileto clinically relevant antibiotics using bottom-up assembly of human gut communities. We identify 2 classes of microbial interactions that alterC.difficile’s antibiotic susceptibility: interactions resulting in increased ability ofC.difficileto grow at high antibiotic concentrations (rare) and interactions resulting inC.difficilegrowth enhancement at low antibiotic concentrations (common). Based on genome-wide transcriptional profiling data, we demonstrate that metal sequestration due to hydrogen sulfide production by the prevalent gut speciesDesulfovibrio pigerincreases the minimum inhibitory concentration (MIC) of metronidazole forC.difficile. Competition with species that display higher sensitivity to the antibiotic thanC.difficileleads to enhanced growth ofC.difficileat low antibiotic concentrations due to competitive release. A dynamic computational model identifies the ecological principles driving this effect. Our results provide a deeper understanding of ecological and molecular principles shapingC.difficile’s response to antibiotics, which could inform therapeutic interventions.