The objective of this study was to explore the molecular mechanism of cadmium stress in watermelon, as well as to promote molecular breeding in watermelon. The composition of watermelon seedling leaves compared by materials of Hexin(HX) and Heimeiniang(HMN) after Cd treatment (CdCl2 60 mg/kg) , followed by HX, HMN, HXCK and HMNCK. The molecular mechanism of cadmium stress in watermelon was studied by transcriptome sequencing using Illumina technique. The results showed that there were a total of 8 579 differentially expressed genes in the treatment group HMN and HMNCK. Among them, there were 4 297 genes significantly up–regulated and 4 282 significantly down–regulated genes. However, there were a total of 7 108 differentially expressed genes compared with HX and HXCK, and there were 3 662 significant up–regulated genes, 3 446 significantly down–regulated genes. The Venn diagram showed that there were 5 656 genes differentially expressed in HMN and HX. According to the annotations from different databases, we found that the differentially expressed genes related to cadmium stress in watermelon mainly including genes related to photosynthesis, signal transduction, secondary metabolism and transcription factors. Transcription factors MYB, AP2 / EREBP, bHLH, NAC and WRKY family may play an important role in watermelon response to cadmium stress. The results were consistent with Illumina sequencing data based by quantitative fluorescence analysis of 7 randomly selected genes was performed by qRT–PCR, which confirmed the validity of differentially expressed gene data.