The frequency of fish encountering hypoxia has risen dramatically as global warming and water pollution intensify, posing a serious threat to survival. Rainbow trout (Oncorhynchus mykiss), which is an economically important fish worldwide, belongs to a typical hypoxia-sensitive fish. However, little is known about the differences in response mechanisms employed by rainbow trout to short-term and chronic hypoxia stress and the roles of non-coding RNAs (ncRNAs) in the response of rainbow trout to hypoxia stress. In this study, we systematically analyzed the changes of liver biochemical parameters in rainbow trout exposed to moderate hypoxic conditions (DO: 4.5 ± 0.1 mg/L) for different durations (4, 8, 12, 24 h and 1 month) and 24 h reoxygenation, and histologic and transcriptome profiles (lncRNA, miRNA and mRNA) under hypoxia stress for 12 h (Tm12L) and 1 month (TmlL) compared with control (normoxia, DO: 8.5 ± 0.1 mg/L), and target and regulatory relationships between LOC110520201, miR-2188-y and superoxide dismutase 1 (sod1) were verified by dual-luciferase reporter, overexpression and silencing assays. Histological observations revealed that liver showed no pathological changes in TmlL. Integrating biochemical parameters and mRNA expression profiles, we found that exposure to short-term hypoxia stress resulted in enhanced immune response, aerobic and anaerobic glycolysis and lipid metabolism. In TmlL, increased anaerobic glycolysis and decreased aerobic glycolysis were observed, and antioxidant and immune capacity has returned to normal. Additionally, several key hypoxia-related genes (epo, vegfc, epor, sod1, ppara, foxo1a, gk, dusp1, nlrc3 and nlrp3) and ceRNA regulatory networks were identified from 2711 differentially expressed (DE) mRNAs, 575 DElncRNAs and 395 DEmiRNAs, including LOC110520201-miR-2188-y-sod1, LOC110533332-miR-144-y-vegfc, LOC110526066-miR-465-x-ppara and LOC110535032-miR-743-y-nlrp3. The analysis of expression patterns in rainbow trout liver and liver cells treated with hypoxia suggested that changes in LOC110520201, miR-2188-y and sod1 showed a ceRNA regulatory relationship. Further experiments demonstrated that sod1 was a target of miR-2188-y, and LOC110520201 silencing increased the expression of miR-2188-y and inhibited sod1 expression. These results facilitate our understanding of the molecular mechanisms of hypoxia response in rainbow trout and provide genetic resources for breeding hypoxia-tolerant varieties.