Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial electron transport chain, and COX6A is one of the nuclear-encoded subunits. To gain insights into the potential function of ) and the related miRNAs, genes, as well as the expression patterns in different tissues and in response to salinity changes were accomplished. In addition, miRNAs which target to cox6a gene was analyzed. The results showed that two , were identified in the spotted sea bass genome. The phylogenetic relationships confirmed their annotations. Multiple sequence alignment suggested that the C-terminal amino acid sequences of COX6A are relatively conserved. The higher expression level of mRNA was detected in the hypophysis, brain, liver, and kidney, while was highly expressed in the heart and kidney. We obtained four candidate microRNAs (miR-30e-5p, miR-223, miR-200a-3p, and miR-155-5p) which target ). Quantitative reverse transcription-PCR (qRT-PCR) results showed that , miR-30e-5p, miR-223, and miR-200a-3p expressed differentially during the low and high salinity environments, while the expression of miR-155-5p only changed significantly in response to the high salinity treatment, indicating that , and the four miRNAs are involved in osmoregulation in the spotted sea bass. During the acute salinity transfer experiment, the expression of miR-30e-5p, miR-223, and miR-200a-3p was negatively correlated with was the strongest, which suggested that miR-30e-5p, miR-223, and miR-200a-3p may be involved in the regulation of gene expression. This study also provides a valuable reference for the comprehensive analysis of the molecular mechanisms of osmotic regulation in fish.