Litchi (Litchi chinensis Sonn.) is an important subtropical and tropical evergreen fruit tree that is seriously affected by chilling stress. In order to identify genes that may be involved in the response to chilling in litchi, we investigate the physiological and biochemical changes under chilling stress and construct 12 RNA-Seq libraries of leaf samples at 0, 4, 8, and 12 days of chilling. The results show that antioxidant enzymes are activated by chilling treatments. Comparing the transcriptome data of the four time points, we screen 2496 chilling-responsive genes (CRGs), from which we identify 63 genes related to the antioxidant system (AO-CRGs) and 54 ABA, 40 IAA, 37 CTK, 27 ETH, 21 BR, 13 GA, 35 JA, 29 SA, and 4 SL signal transduction-related genes. Expression pattern analysis shows that the expression trends of the 28 candidate genes detected by qRT-PCR are similar to those detected by RNA-Seq, indicating the reliability of our RNA-Seq data. Partial Least Squares Structural Equation Modeling (PLS-SEM) analysis of the RNA-Seq data suggests a model for the litchi plants in response to chilling stress that alters the expression of the plant hormone signaling-related genes, the transcription factor-encoding genes LcICE1, LcCBFs, and LcbZIPs, and the antioxidant system-related genes. This study provides candidate genes for the future breeding of litchi cultivars with high chilling resistance, and elucidates possible pathways for litchi in response to chilling using transcriptomic data.