BilR is a gut microbial enzyme that reduces bilirubin to urobilinogen. This study identifies BilR as a key enzyme in the gut microbiota responsible for the reduction of bilirubin, a critical step in the haem degradation pathway. The enzyme was identified through biochemical analyses and comparative genomics, revealing that BilR is predominantly encoded by Firmicutes species. Analysis of human gut metagenomes showed that BilR is nearly ubiquitous in healthy adults but less prevalent in neonates and individuals with inflammatory bowel disease (IBD). The discovery highlights the role of the gut microbiome in bilirubin metabolism and the importance of the gut–liver axis in maintaining bilirubin homeostasis. BilR is a bilirubin reductase that acts on carbon–carbon double bonds, reducing bilirubin to urobilinogen. The enzyme was confirmed to be sufficient to confer bilirubin reductase activity through heterologous expression in E. coli. The study also delineated the BilR clade, identifying key residues critical for bilirubin reduction. The presence of BilR was found to be absent in neonates during the period of highest jaundice risk but present by the end of the first year of life. In patients with IBD, the prevalence of BilR was significantly lower, suggesting a disruption in bilirubin metabolism. The findings underscore the importance of gut microbial bilirubin reduction in maintaining bilirubin homeostasis and its implications for human health. The study provides foundational knowledge for future investigations into the role of bilirubin metabolism in human health.BilR is a gut microbial enzyme that reduces bilirubin to urobilinogen. This study identifies BilR as a key enzyme in the gut microbiota responsible for the reduction of bilirubin, a critical step in the haem degradation pathway. The enzyme was identified through biochemical analyses and comparative genomics, revealing that BilR is predominantly encoded by Firmicutes species. Analysis of human gut metagenomes showed that BilR is nearly ubiquitous in healthy adults but less prevalent in neonates and individuals with inflammatory bowel disease (IBD). The discovery highlights the role of the gut microbiome in bilirubin metabolism and the importance of the gut–liver axis in maintaining bilirubin homeostasis. BilR is a bilirubin reductase that acts on carbon–carbon double bonds, reducing bilirubin to urobilinogen. The enzyme was confirmed to be sufficient to confer bilirubin reductase activity through heterologous expression in E. coli. The study also delineated the BilR clade, identifying key residues critical for bilirubin reduction. The presence of BilR was found to be absent in neonates during the period of highest jaundice risk but present by the end of the first year of life. In patients with IBD, the prevalence of BilR was significantly lower, suggesting a disruption in bilirubin metabolism. The findings underscore the importance of gut microbial bilirubin reduction in maintaining bilirubin homeostasis and its implications for human health. The study provides foundational knowledge for future investigations into the role of bilirubin metabolism in human health.