Medicinal plants are still less expensive, safe to non‐target organisms, and eco‐friendly. The present work aims to evaluate the molluscicidal activity of the methanolic extract of Ziziphus spina‐christi and Carica papaya seeds against Biomphalaria alexandrina snails. The half lethal concentrations (LC50) of Z. spina‐christi and C. papaya were 108 and 138.5 mg/L, respectively after 24 h. LC10 of C. papaya created a pronounced induction in catalase (CAT) activity, while LC25 of Z. spina‐christi and LC50 of C. papaya induced an inhibition in superoxide dismutase (SOD) level in treated snails. LC25 of Z. spina‐christi caused the highest induction in total antioxidant capacity (TAC). Phagocytic indices values were the lowest in snails exposed to LC50 of both Z. spina‐christi and C. papaya. Considerable changes in DNA patterns were observed in all treated groups by RAPD‐PCR using six primers. The similarity indices of snails exposed to Z. spina‐christi were higher than those exposed to C. papaya. Results showed no mortality in Daphnia magna individuals during the first 12 h of the experiment, while the extract of C. papaya seeds was more toxic on D. magna than Z. spina‐christi after 24 h of the exposure.