Abstract Background: Despite the global efforts to control schistosomiasis, still prevalence in endemic regions unchanged. The present study was conducted to investigate the possible role of artesunate (AS) and praziquantel (PZQ) combination in enhancing cure in pre-patent and patent Schistosoma mansoni infection, and study the role of apoptosis in evaluation of the drugs efficacy. Methods: Eighty laboratory-bred Swiss albino male mice were classified into four groups (20 mice each); control, PZQ treated (500 mg/kg), AS treated (400 mg/kg) and combined AS (400 mg/kg) + PZQ (500 mg/g) groups. Efficacy of the drugs was assessed by parasitological (egg count/gram stool, worm burden, tissue egg load, oogram pattern), histopathological (haematoxylin and eosin –for detection of type of hepatic granulomas, number & diameter) and immunohistochemical studies (P53 and Bcl-2 markers for determination of inflammatory cells and the degree of apoptosis). Results: Significant reduction was recorded in stool egg count, tissue egg count (liver and intestine), worm burden, granuloma number and size and changed oogram patterns in artesunate -praziquantel combined group followed by artesunate monotherapy group. There was a significant increase in the apoptotic proteins P53 and slight increase in anti-apoptotic proteins Bcl-2 in the infected group compared to the control healthy group. A significant decrease and increase in P53 & Bcl-2 expressions respectively were observed in artesunate – praziquantel combined group compared to control infected group. Conclusion: artesunate-praziquantel combination is a potential upcoming chemotherapy for schistosomiasis mansoni. Both Bcl-2 and P53 are good markers assessing S. mansoni apoptosis, morbidity and chemotherapy efficacy.