Sweet sorghum is a C4 crop that can be grown for silage forage, fiber, syrup and fuel production. It is generally considered a salt-tolerant plant. However, the salt tolerance ability varies among genotypes, and the mechanism is not well known. To further uncover the salt tolerance mechanism, we performed comparative transcriptome analysis with RNA samples in two sweet sorghum genotypes showing different salt tolerance abilities (salt-tolerant line RIO and salt-sensitive line SN005) upon salt treatment. These response processes mainly focused on secondary metabolism, hormone signaling and stress response. The expression pattern cluster analysis showed that RIO-specific response genes were significantly enriched in the categories related to secondary metabolic pathways. GO enrichment analysis indicated that RIO responded earlier than SN005 in the 2 h after treatment. In addition, we identified more transcription factors (TFs) in RIO than SN005 that were specifically expressed differently in the first 2 h of salt treatment, and the pattern of TF change was obviously different. These results indicate that an early response in secondary metabolism might be essential for salt tolerance in sweet sorghum. In conclusion, we found that an early response, especially in secondary metabolism and hormone signaling, might be essential for salt tolerance in sweet sorghum.