Hair arsenic and cadmium from 339 women with congenital heart defect (CHD)-affected pregnancies (case women) and 333 women with normal live births (control women) in China were estimated using inductively coupled plasma mass spectrometry. The median levels of hair arsenic and cadmium in the case women were 98.30 (74.30–136.30) ng/g and 14.60 (8.30–32.50) ng/g, respectively, which were significantly higher than the levels in the control group (P < 0.05). Arsenic concentrations ≥62.03 ng/g were associated with increased risk for almost every CHD subtype, with a dose-response relationship. However, only the group with the highest cadmium levels (≥25.85 ng/g) displayed an increased risk of CHDs (AOR 1.96; 95% CI 1.24–3.09), with a 2.81-fold increase found for the occurrence of conotruncal defects in their offspring. Furthermore, an interaction between arsenic and cadmium was observed. Our findings suggest that maternal exposure to arsenic and cadmium may be a significant risk factor for CHDs in offspring. Cadmium may have an enhancing effect on the association between arsenic and the risk of CHDs in offspring.