The Fujian oyster, Crassostrea angulata, accounts for approximately 50% of the total oyster production in China and is one of the most economically important marine products. In this study, we investigated differential gene expression profiles between diploid (n = 2) and triploid (n = 3) oysters that may indicate the specific adaptation associated with ploidy. A total of 14,626,126 and 15,492,551 reads were generated from diploid and triploid oyster muscle transcriptomes using Illumina RNA-Seq respectively. Gene expression analysis revealed a total of 2,045 differentially expressed genes between 2n and 3n individuals, from which 814 genes were significantly up-regulated in the 2n transcriptome while 1,231 were down-regulated. In addition, 24 differentially expressed genes (DEGs) were uniquely expressed in 2n individuals while 28 DEGs were uniquely expressed in 3n individuals. Furthermore, our pathway analysis suggested that the DEGs up-regulated in 2n oysters were enriched in the pathways related to normal growth, development and reproduction, whereas DEGs up-regulated in 3n individuals may be involved in faster growth and metabolism. Finally, we validated the expression levels of 15 genes using quantitative real-time PCR (qRT-PCR), and 14 out of 15 genes showed consistent expression patterns with RNA-Seq data. This study provides an important foundation for further investigations on distinct gene expression patterns and signalling pathways that differ between diploid and triploid oysters.