Background Tuberous root formation and development is a complex process in sweet potato, which is regulated by multiple genes and environmental factors. However, the regulatory mechanism of tuberous root development is unclear. Results In this study, the transcriptome of fibrous roots (R0) and tuberous roots in three developmental stages (Rl, R2, R3) were analyzed in two sweet potato varieties, GJS-8 and XGH. A total of 22,914 and 24,446 differentially expressed genes (DEGs) were identified in GJS-8 and XGH respectively, 15,920 differential genes were shared by GJS-8 and XGH. KEGG pathway enrichment analysis showed that the DEGs shared by GJS-8 and XGH were mainly involved in “plant hormone signal transduction” “starch and sucrose metabolism” and “MAPK signal transduction”. Trihelix transcription factor (Tai6.25300) was found to be closely related to tuberous root enlargement by the comprehensive analysis of these DEGs and weighted gene co-expression network analysis (WGCNA). Conclusion A hypothetical model of genetic regulatory network for tuberous root development of sweet potato is proposed, which emphasizes that some specific signal transduction pathways like “plant hormone signal transduction” “Ca2+signal” “MAPK signal transduction” and metabolic processes including “starch and sucrose metabolism” and “cell cycle and cell wall metabolism” are related to tuberous root development in sweet potato. These results provide new insights into the molecular mechanism of tuberous root development in sweet potato.