Commercially available St. John’s wort supplement (SJWS) composed of an herbal mixture of St. John’s Wort (SJW), Rosemary (RM) and Spirulina (SP) is used as a dietary supplement for the treatment of psychiatric disorders. Although the minor ingredients, (RM and SP) are proven antioxidants, their quantity is quite insignificant as compared to the SJW, which is the major ingredient. Most of the toxic effects of SJWS are attributed to the main constituents of SJW which differ due to the influence of light (hypericin) and variations in temperature above freezing point (hyperforin). However, there are no reports on toxicity of SJWS maintained at room temperature in pharmacies and supermarkets. In view of the folkloric importance, immense (prescribed or unprescribed) use and a paucity of literature on SJWS, it was found worthwhile to (1) determine the genotoxic effects of SJWS in somatic and germ cells of mice and (2) investigate the role of biochemical changes, as a possible mechanism. The protocol included the oral treatment of mice with different doses (380, 760 and 1520 mg/kg/day) of SJWS for 7 days. The following experiments were conducted: (i) cytological studies on micronucleus test, (ii) cytogenetic analysis for meiotic chromosomes, (iii) cytological analysis of spermatozoa abnormalities, (iv) quantification of proteins and nucleic acids in hepatic and testicular cells and (v) estimation of malondialdehyde (MDA) and nonprotein sulfhydryl (NP-SH) in hepatic and testicular cells. The treatment increased the frequency of micronuclei in polychromatic erythrocytes (PCE) in the femora. It caused aberrations in chromosomes of testes and induced spermatozoa abnormalities. These changes might be attributed to the epigenetic mechanisms as revealed by an increase in concentrations of MDA and depletion of nucleic acids and NP-SH levels in both hepatic and testicular cells observed in the present study. Since, the samples of SJWS used were not drawn from extremities of light and temperature; the observed effect might not be related to the main constituents of SJW. However, these changes might be ascribed to the combined effect of terpenes, tannins, quercetin and flavonoids present in SJW.