Significance Vitamin B12 and folic acid (FA) deficiencies present with symptoms like anemia and birth defects, but the underlying mechanism remains unclear. Here, we show that B12 and FA antagonize aryl hydrocarbon receptor (AhR), which has been implicated in anemia and birth defects. We found that treatments with B12/FA rescued mice from AhR agonist-mediated anemia, fatty livers, and cleft palates. B12/FA-deficient mice exhibited higher AhR transcriptional activity and faulty erythropoiesis that were abrogated with AhR deficiency. Last, we verified that human samples lacking functional B12/FA uptake exhibit higher expression of AhR target genes and lower transcription of pathways implicated in birth defects. Our study provides a parsimonious explanation for how deficiency symptoms arise and informs other comorbidities driven by AhR hyperstimulation.