The commercial value of red tilapia is hampered by variations in skin color during overwintering. In this study, three types of skin of red tilapia, including the skin remained pink color during and after overwintering (P), the skin changed from pink color to black color during overwintering and remained black color after overwintering (P-B), and the skin changed from pink color to black color during overwintering but recovered to pink color when the temperature rose after overwintering (P-B-P), were used to analyze their molecular mechanisms of color variation. The transcriptome results revealed that the P, P-B, and P-B-P libraries had 43, 42, and 43 million clean reads, respectively. The top 10 abundance mRNAs and specific mRNAs (specificity measure SPM > 0.9) were screened. After comparing intergroup gene expression levels, there were 2528, 1924, and 1939 differentially expressed genes (DEGs) between P-B-P and P-B, P-B-P and P, and P-B and P, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of color-related mRNAs showed that a number of DEGs, including tyrp1, tyr, pmel, mitf, mc1r, asip, tat, hpdb, and foxd3, might play a potential role in pigmentation. Additionally, the co-expression patterns of genes were detected within the pigment-related pathways by the PPI network from P-B vs. P group. Furthermore, DEGs from the apoptosis and autophagy pathways, such as baxα, beclin1, and atg7, might be involved in the fading of red tilapia melanocytes. The findings will aid in understanding the molecular mechanism underlying skin color variation in red tilapia during and after overwintering as well as lay a foundation for future research aimed at improving red tilapia skin color characteristics.