Gene electrotransfer upregulate DNA pattern recognition receptors or DNA sensors, which are part of the innate immune system. In this study, we tested if addition of the cocktail of innate immune system inhibitors to the cells during gene electrotransfer (GET) can increase transfection efficiency and cell survival. The results indicate that this cocktail can decrease cytosolic DNA sensors expression after GET, and consequently increase cell survival and transfection efficiency in B16 cells, but only in highly metastatic B16F10 subtype. We demonstrated that DNA sensors expression during the transfection methods needs to be downregulated if higher transfection efficiency and better cells’ survival is needed. The inhibition of the receptors of the innate immune system can improve the transfection efficiency also for GET of malignant melanoma B16 cells, but only of highly metastatic subtype.