Emerging evidence indicates an association between the gut microbiota and the incidence of osteonecrosis (ON), yet the literature has not adequately addressed whether this relationship is causal. This study uses data from the MiBioGen Consortium and the UK Biobank for Mendelian randomization (MR) analysis to identify pathogenic gut microbial taxa associated with ON. Sensitivity analyses confirmed causal relationships, while reverse MR ruled out reverse causation. SNP annotation located genetic variants linked to gut microbiota instrumental variables in ON. The inverse variance weighted method revealed 5 microbial taxa with a causal association with ON, including the order Erysipelotrichales (OR = 2.24, 95% CI = 1.16-4.32, P = .02), genus Christensenellaceae R (OR = 0.41, 95% CI = 0.19-0.87, P = .02), family Erysipelotrichaceae (OR = 2.24, 95% CI = 1.16-4.32, P = .02), family Family XIII (OR = 0.45, 95% CI = 0.21-0.95, P = .04), and class Erysipelotrichia (OR = 2.24, 95% CI = 1.16-4.32, P = .02). Sensitivity analyses mitigated concerns regarding heterogeneity, directional pleiotropy, and outliers (P >
.05). However, the reverse MR showed no causal effect of ON on these taxa. SNP (single-nucleotide polymorphism) annotation pinpointed 20 host genes associated with ON pathogenesis. These findings lay the groundwork for microbiota-targeted therapies and deepen our understanding of the gut-bone axis in osteonecrosis.