Purpose: Explore the regulatory function of sodium hydrosulfide (NaHS) on the proliferation and apoptosis of exogenous SB203580 pre-treated human ovarian cancer SKOV3 cells. Methods: SKOV3 cells cultured in vitro were assigned to the control group, NaHS group, SB203580 group, and NaHS combined with SB203580 group. The effects and influences on cell proliferation were detected by MTT assay. Effects on the cell cycle and apoptosis were detected by flow cytometry. Western blot was used to detect the expression of P-p38MAPK. Results: Proliferation of SKOV3 cells were remarkably decreased in the NaHS, SB203580, and NaHS combined with SB203580 groups. Cell quantity in G1 phase and S phase increased and decreased remarkably, respectively. Obviously, cell apoptosis rate was increased in the combination group compared to single-drug treatment groups. P-p38MAPK expression in NaHS group was upregulated by comparing with that in control group, and that was markedly enhanced in the combination group compared to single-drug treatment group. Conclusions: NaHS inhibited proliferation and promoted apoptosis of SKOV3 cells by blocking the p38MAPK signaling pathway. Furthermore, coordination between NaHS and SB203580 regulated the proliferation and apoptosis of SKOV3 cells.