An increasing number of studies have shown that the promising compound resveratrol treats multiple diseases, such as cancer and aging; however, the resveratrol mode-of-action (MoA) remains largely unknown. Here, by virtue of multiple omics approaches, we adopted fission yeast as a model system with the goal of dissecting the common MoA of the anti-proliferative activity of resveratrol. We found that the anti-proliferative activity of resveratrol is mainly due to its unique role of inhibiting the separation of sister cells, similar phenotype with the C2H2 zinc finger transcription factor Ace2 knock-out strain. Microarray analysis shown that resveratrol has extensive impact on the fission yeast transcription levels. Among the changed gene's list, 40% of up-regulated genes are Core Environmental Stress Responses genes, and 57% of the down-regulated genes are periodically expressed. Moreover, resveratrol leverages the metabolome, which unbalances the intracellular pool sizes of several classes of amino acids, nucleosides, sugars and lipids, thus reflecting the remodulated metabolic networks. The complexity of the resveratrol MoA displayed in previous reports and our work demonstrates that multiple omics approaches must be applied together to obtain a complete picture of resveratrol's anti-proliferative function.