Background <p>Excessive exposure to heavy metals has been linked to various health problems, including organ damage, neurological disorders, and reproductive and developmental abnormalities. However, the relationship between heavy metals exposure and uterine fibroids remains uncertain. To explore this association, we conducted a cross-sectional study among American women.</p> Methods <p>We utilized data from three cycles of the National Health and Nutrition Examination Survey (NHANES, 1999–2006) to evaluate the association between uterine fibroids and blood heavy metal levels, including lead (Pb), cadmium (Cd), and mercury (Hg). Weighted logistic regression, restricted cubic spline (RCS), Bayesian kernel machine regression (BKMR), and subgroup analyse were used to examine the potential relationships between blood heavy metals and uterine fibroids.</p> Results <p>Of the 4502 American women studied, 542 (12.04%) had uterine fibroids. Elevated levels of all heavy metals were significantly more common in women with uterine fibroids (<i>P</i> &lt; 0.001). Blood Hg levels were notably associated with uterine fibroid prevalence in the adjusted model (OR = 1.41, 95% CI: 1.06–1.89, <i>p</i> = 0.03). Similar patterns were partly observed for blood Pb and Cd. Age and marital status were significant interaction factors concerning Hg exposure (<i>P</i> for interaction &lt; 0.05). A dose-response relationship with an inflection point at 7µmol/L was identified for Hg, and BKMR models indicated a positive association between mixed heavy metal exposure and uterine fibroid risk.</p> Conclusions <p>Exposure to blood heavy metals, particularly Hg, is significantly associated with an elevated risk of uterine fibroids. Further prospective studies are necessary to confirm these findings.</p>