In the study, zebrafish were exposed to 0 and 200 μg/L Zn for 8 weeks, and then both groups were transferred to water including 0, 100, and 200 μg/L Cd for 4 days, respectively. Acute Cd exposure caused negative effects on stress defense, immune, and metal transport systems by increasing lipid peroxidation, iNOS activity and mRNA levels of il-6 and inos, and decreasing Cu/Zn-SOD and HSP70 levels, and mRNA levels of sod1, cat, hsp70, p65, mtf-1, znt5, zip7, atp7a, and atp7b. Lipid peroxidation was significantly reduced by Zn pre-exposure under Cd exposure, which may be explained by the enhanced stress defense capacity and the weaken inflammatory response. Firstly, Zn pre-exposure increased MTs and HSP70 levels and CAT activity in Cd-free water, which may facilitate fish quick response to Cd. Secondly, Zn pre-exposure reduced Cd accumulation at 100 and 200 μg/L Cd, down-regulated il-6 and il-1β at 100 μg/L Cd and p65 at 200 μg/L Cd, and increased Cu/Zn-SOD and CAT activities at 200 μg/L Cd. Thirdly, Zn pre-exposure alone up-regulated transcription factors (hsf1, hsf2, and mtf-1, and nrf2) and their target genes (sod1, cat, hsp70, and mt2) under Cd exposure in a dose-dependent manner. It should be noted that Zn pre-exposure down-regulated several metal transport genes dramatically at 0 and 100 μg/L Cd, which may be an important mechanism for reducing Cd import into livers. Overall, long-term and environmental Zn pre-exposure mitigated Cd toxicity by the enhanced stress defense capacity and the down-regulated metal transport and inflammatory responses.