In systemic therapy, chemotherapeutic drugs, often, cause considerable side effects; and combination of natural compounds lessen the extent of such effects. In the present study, combined effect of citral and 5-fluorouracil was studied in Schizosaccharomyces pombe cells. The antagonistic combination index found was at 0.01 and 0.025 mM of citral with 40 μg or higher concentration of 5-fluorouracil. The combined treatment was so effective that higher number of cells underwent apoptosis compared to individual treatment of 5-fluorouracil. Citral controlled ROS levels and increased survival of normal cells. Several differentially expressed proteins observed in the citral treatment could further help understanding its mechanism of action.