The Wnt signaling pathway is an evolutionarily conserved signaling pathway that plays essential roles in embryonic development, organogenesis, and many other biological activities. Both Wnt proteins and DIX proteins are important components of Wnt signaling. Systematic studies of Wnt and DIX families at the genome-wide level may provide a comprehensive landscape to elucidate their functions and demonstrate their relationships, but they are currently lacking. In this report, we describe the correlations between mouse Wnt and DIX genes in family expansion, molecular evolution, and expression levels in cardiac hypertrophy at the genome-wide scale. We observed that both the Wnt and DIX families underwent more expansion than the overall average in the evolutionarily early stage. In addition, mirrortree analyses suggested that Wnt and DIX were co-evolved protein families. Collectively, these results would help to elucidate the evolutionary characters of Wnt and DIX families and demonstrate their correlations in mediating cardiac hypertrophy.