Ocimum basilicum L. sweet basil is well known plant with aromatic, culinary, and medicinal properties, which has been mostly investigated to produce terpenoids and polyphenols. Extreme temperature and other abiotic stresses linked to climatic changes threatens to negatively impact the productivity of sweet basil, causing decreased yields and loss in polyphenols quality, especially during later stages of development. At present, only a sparse collection of genomic resources and annotations exists for sweet basil [1,2], a tetraploid (2n = 4x = 48) with a highly polymorphic structure. Here we performed de novo transcriptome sequencing of O. basilicum under controlled environmental conditions to simulate several abiotic stresses. The objective of the study is the identification of candidate genes involved in transcriptional response to abiotic stress critical for differential accumulation of phenylpropanoids and terpenoids in biosynthetic pathways. The differential gene expression response was assessed under 10 stress treatments including high CO2, high UV-B, low temperature (LT), high temperature (HT), and drought (DS) to identify the most significant transcriptional and metabolism changes, focusing on essential oil production. Abiotic stress treatments were applied individually or in combinations of two to mimic global climatic changes. Using O. basilicum reference transcriptome, acomparative genomic analysis identified 36,880 (16,348 unique genes) significantly differentially expressed genes across treatments by using DESeq2 package. Abiotic stresses associated with global climate change (+CO2 and +UV-B) acted independently and increased the percentage of DEGs when added to typical abiotic stresses (LT, HT, DS). Out of all treatments, +CO2+LT (7,691) and LT (4,722) showed the largest number of DEGs, followed by DS (2,594), +CO2+DS (2,094), +CO2+HT (2,120), and HT (1,601), while +CO2+UV-B (1,340), and UV-B (232) showed the weakest transcriptional reprogramming effect. 1,522 differentially expressed genes found were common in all three LT treatments. 53% of the differentially expressed genes in +CO2+LT, and +CO2+DS treatments functionally annotated with EggNOG were represented in Gene Ontology enrichment analysis, with 21% genes involved in cellular processes and signaling, and 26% genes involved in metabolism including biosynthesis pathways by using. Our DEG TF analysis revealed their regulatory functions in plant stress responses and in regulation of secondary metabolism. KEGG pathway analysis indicated DEGs involved in phenylpropanoid biosynthesis pathway, one of the contributing factors of aroma and flavor in O. basilicum. 12 bHLH TFs identified in LT stress linked this family to phenylpropanoid biosynthesis regulation. The analysis also revealed differentially expressed genes involved in terpenoid biosynthesis: 118 differentially expressed genes in LT treatment were identified as Cytochrome P450 enzymes, a gene superfamily involved in terpenoids biosynthesis in plants. In conclusion, this study contributes regulatory transcriptomic analyses of genes and metabolites associated with biosynthesis and regulation of terpenoids and phenylpropanoid, providing new insights into the molecular mechanisms of stress responses in sweet basil.