Metallic elements are ubiquitous in the natural environment and always collaborate to affect human health. The relationship of handgrip strength, a marker of functional ability or disability, with metal co-exposure remains vague. In this study, we aimed to investigate the effect of metal co-exposure on sex-specific handgrip strength. A total of 3594 participants (2296 men and 1298 women) aged 21 to 79 years recruited from Tongji Hospital were included in the present study. Urinary concentrations of 21 metals were measured by inductively coupled plasma mass spectrometer (ICP-MS). We used linear regression, restricted cubic spline (RCS) model, and weighted quantile sum (WQS) regression to evaluate the association of single metal as well as metal mixture with handgrip strength. After adjusting for important confounding factors, the results of linear regression showed that vanadium (V), zinc (Zn), arsenic (As), rubidium (Rb), cadmium (Cd), thallium (Tl), and uranium (U) were adversely associated with handgrip strength in men. The results of RCS showed a non-linear association between selenium (Se), silver (Ag), and nickel (Ni) with handgrip strength in women. The results of WQS regression revealed that metal co-exposure was inversely related to handgrip strength for men (β = -0.65, 95% CI: -0.98, -0.32). Cd was the critical metal in men (weighted 0.33). In conclusion, co-exposure to a higher level of metals is associated with lower handgrip strength, especially among men, and Cd may contribute most to the conjunct risk.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.