Withania somnifera, commonly referred to as Indian Ginseng, is a medicinally important plant that can be found in many regions of the world, such as South Africa and India. Withanolides are key secondary metabolites responsible for conferring the plant its unique medicinal properties. The reaction of W. somnifera to salt stress, in particular the possible effects on its withanolide production, have yet to be explored. Under salt stress, germination efficiency dropped by 17.8% and caused physiological damage to emerging roots. A transcriptome analysis of salt stressed leaves revealed the differential regulation of 3 048 transcripts, with gene ontology analysis indicating an increased detoxification response concomitant with reduced growth, energy metabolism and protein modification. Notably, 26 transcription factor families, particularly AP2/ERF, NAC, GRAS and HB-WOX members as well as 10 Late Embryogenesis-Abundant members, predominantly dehydrins, were significantly differentially regulated, suggesting their potential involvement in the salt stress response of W. somnifera. Although the withanolide pathway genes showed limited response to the salt treatment, three genes in the pathway (HMGS, FPPS and WsCYP98A) were significantly downregulated. This study provides valuable insights into the molecular responses of W. somnifera to salt stress, highlighting potential targets for future research and subsequently for withanolide production which has vast potential in pharmaceutical industry.