The prevalence of the applications of nanomaterials in consumer products and water treatment facilities increases the chance that humans will be exposed to both nanoparticles and environmental pollutants such as heavy metals. Co-exposure to nanoparticles and heavy metals may adversely affect human health, especially in susceptible populations such as overweight subjects. To evaluate the impact of such co-exposures, we orally administered zinc oxide nanoparticles (ZNPs; 14 or 58 nm) and/or Pb(Ac)2 at tolerable doses to both healthy overweight and healthy normal weight mice. The ZNPs enhanced the deposition of Pb in all major organs in the overweight mice compared with that in the normal mice. As a result, higher levels of hepatic reactive oxygen species, pro-inflammatory cytokines, and liver injury were observed in the overweight mice but not in the normal weight mice. Our findings underscore a potentially enhanced risk of nanoparticle/heavy metal co-exposure in the susceptible overweight population.