Hypoxia often induces inflammatory in fish, likely due to disrupted ion homeostasis and DNA damage. Chromium (Cr3+), as an essential trace element for animals, aids DNA repair and regulates ion homeostasis. However, whether Cr3+ could alleviate hypoxia-induced liver inflammation by regulating ion homeostasis or reducing DNA damage is unknown, which is the purpose of this study. A total of 2160 juvenile grass carp (10.98 ± 0.01 g) were randomized to 6 treatments. The fish were fed diets containing Cr3+ at concentrations of 0.25 (basal diet), 0.67, 1.08, 1.63, 2.08, and 2.65 mg/kg for 70 d. Then, 96 fish were selected, randomized to control (n = 48) or hypoxia (n = 48) groups, and subjected to hypoxia stress for 96 h. The results showed that: (1) In the hypoxia group, Cr3+ inhibited the gene expression of pro-inflammatory cytokines and pyroptosis-related factors, while it enhanced the gene expression of anti-inflammatory cytokines. This indicated that Cr3+ alleviated hypoxia-induced liver inflammatory responses. (2) Cr3+ reduced the relative content of mitochondrial DNA (mtDNA) in the cytoplasm of the hypoxia group (P < 0.05), which suggested that Cr3+ had a potential benefit in alleviating DNA damage. (3) In the hypoxia group, Cr3+ suppressed the expression of proteins associated with K+ and Cl- efflux and promoted the expression of proteins related to K+ and Cl- influx, thereby contributing to ion homeostasis. In summary, Cr3+ likely maintained ion homeostasis and preserved mtDNA integrity, thereby suppressing liver inflammatory responses, which may provide a novel nutritional regulation strategy for enhancing hypoxia stress resistance in fish.