Chlorella vulgaris is an important freshwater alga that is widely used as a food source for humans and animals. High-salinity environments can cause accumulation of lipids and proteins in this species, but the mechanism of this accumulation and the salt response remain unclear. In this work, transcriptome analysis was performed for the C. vulgaris response to salt stress (1% and 3% NaCl) applied for different times (2 h and 4 h). In total, 5232 and 9196 were differentially expressed after 1% NaCl for 2 and 4 h, and 3968 and 9035 unigenes were differentially expressed after 3% NaCl for 2 and 4 h, respectively. The number of upregulated genes after 4 h of salinity stress was greater than the number of downregulated genes, suggesting that the alteration of gene expression may be related to a mechanism of adaptation to a high-salinity environment. Furthermore, gene ontology and KEGG pathway analyses revealed that numerous biological pathways are affected by salt stress. Among the upregulated pathways, the cytoplasmic calcium signaling pathway, which is involved in the regulation of homeostasis, was highly upregulated. Genes involved in the photosystem I light-harvesting pathway were downregulated under salt stress. These results provide foundational information on the effects of salt stress on C. vulgaris metabolism and its possible mechanism of surviving high concentrations of NaCl.