Sinularin, a soft corals-derived natural product, exerts anti-tumorigenic activity in various types of human cancer cells. However, the action of Sinularin and its mechanism in renal carcinoma is not well understood. In the current study, we demonstrated that Sinularin inhibited the viability of human renal cancer cells 786-O and ACHN in a dose- and time-dependent manner, but did not show significant toxicity against non-malignant HRCEpic cells. Cell cycle analysis revealed that Sinularin induced G2/M arrest significantly. In addition, Sinularin could induce apoptosis in cells along with caspase-3/-9 activation, release of mitochondrial proteins, up-regulation of pro-apoptotic Bcl-2 family proteins and inhibition of anti-apoptotic Bcl-2 family proteins. Sinularin could also repress the activation of PI3K/Akt/mTOR signaling pathway. Moreover, Sinularin triggered the activation of MAPKs and p38 activation was essential for the anti-tumor effect of Sinularin. The generation of ROS (reactive oxygen species) was critical for Sinularin-induced apoptosis since ROS scavenger NAC (N-acetyl cysteine) could block the Sinularin-triggered apoptosis. In conclusion, all the results indicated that Sinularin may be applied as a therapeutic natural agent for human renal cancer.