The shell color of marine bivalves shows great diversity and is considered as an economic trait. In China, the hard clam, Mercenaria mercenaria, commonly has three shell colors in the wild: red, white, and mottled. The genetic mechanisms controlling color segregation are not fully understood. In this study, RNA-seq was performed to exploit the related shell color genes and determine the genetic basis of the different shell colors. Nine sequence libraries with those three shell colors of hard clam were constructed; 406,377 transcripts and 248,251 unigenes were obtained with N50 values of 1365 and 1682 base pairs, respectively. Cluster analysis identified 363, 392, and 220 genes exclusively highly expressed in red, white, and mottled clams, respectively. We further classified differentially expressed genes (DEGs), the genes involved in lipid binding and transport, signal transduction, ATP synthesis, and other processes in the red vs white comparison were found, which may participate in red shell formation. DEGs related to signal transduction, particularly G protein-coupled receptor activity, were found in the red vs mottled comparison, suggesting that these genes might be important in mottled shell formation. In the white vs mottled comparison, DEGs involved in zinc ion binding were found. Our results provide new insights into shell color formation mechanisms in molluscs. This information could be used in selective breeding and marker-assisted breeding of this economically important clam species.