To investigate the effects of hypoxia on the liver of triploid rainbow trout (Oncorhynchus mykiss), we integrated transcriptomic and bioinformatics analyses to decipher the regulatory roles of miRNAs and their target genes under hypoxic conditions. Comparative analyses identified 45 differentially expressed miRNAs (DEmiRNAs) between the hypoxic (group D) and normoxic (group E) groups, as well as 117 hypoxia-associated miRNA-mRNA pairs that exhibited negative regulatory interactions. A systematic miRNA-mRNA interaction network was subsequently constructed to visualise these relationships. Gene Ontology (GO) enrichment analyses showed that target genes of DEmiRNAs were mainly enriched in immune system processes and stimulus-response biological functions. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis further showed that vascular endothelial growth factor (VEGF) and ErbB co-activate the downstream MAPK cascade, which plays a crucial role in regulating hepatocyte metabolism, survival, and hypoxia tolerance. The coordinated action of these three pathways together mediates hypoxic stress adaptation in rainbow trout. These findings deepen our understanding of the molecular mechanisms of hypoxic stress in rainbow trout.