The stability of genomic sequences is indispensable for the perpetuation of life of living organisms. Mutagenesis, however, leads to evolution and introduction of genetic variations, desirable or undesirable though, thereby leading to disturbance of cellular metabolic homeostasis. Resulting chromosomal aberrations lead to various disorders and diseases, autoimmune deficiencies, malignancies, senescence, and cancers of different types. Deviations in this intricate system of cells for DNA repair and tolerance are attributable to both exogenous and endogenous damaging sources. n-3-polyunsaturated fatty acids (PUFA), omega-3 fatty acids, alpha-linolenic acid (ALA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) from diverse plant and animal sources taken as supplements, repair damaged DNA through suppression of reactive oxygen species (ROS) generation pathways, by activating certain polymerase enzymes, by reducing telomere shortening. Production of triglycerides (TGs), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL) is lowered by modulating free radical generation pathways by exploiting the antioxidative potential of fish oil. This is attributed to the low production of inflammatory cytokines and interleukins. The chapter delineates the mechanisms of repair of damaged DNA via omega-3 fatty acids. Further elucidation of different pathways to rescue the DNA damage and to reduce genotoxic stress is a much-needed area for future investigations.