Schistosomiasis is a fatal parasitic disease caused by trematode worms of the genus Schistosoma. Bee venom (BV) was used as a potential drug for many diseases due to its pharmacologically active molecules. The major biopeptides of Apis mellifera V are melittin (MEL) and phospholipase A2 (PLA2) which have a wide range of biological activities. The present in vitro study aimed to elucidate the anti-inflammatory effects of MEL and PLA2 on murine splenocytes activated with Schistosoma mansoni egg and worm antigens (SEA and SWA). Splenocytes were collected from the spleen of Balb/c mice, and then cultured in the presence of MEL or PLA2. Proliferation was estimated by MTT assay. Levels of tumor necrosis factor-α (TNF-α), Interleukin-10 (IL-10) and nuclear factor-κB (NF‐κB) were estimated by enzyme-linked immunosorbent assay (ELISA). MEL and PLA2 induced proliferation of murine primary splenocytes in a concentration and time-dependent pattern, where the proliferation of 24 h incubated splenocytes was significantly (p < 0.05) increased at 0.5 μg/ml and 0.05 μg/ml concentrations of MEL and PLA2, respectively compared to non-stimulated cells. The results indicated that MEL and PLA2 modulate an inflammatory reaction by decreasing the levels of both TNF-α and NF‐κB and significantly elevating IL-10 levels. These results may suggest their potent anti-inflammatory effects that can be applied in the treatment of many inflammatory diseases including S. mansoni infection. Further, in vivo studies are required to confirm these results.