Marine organisms derived extracts have been shown to exert multiple anti-cancer activities. Two marine sponge species; finger-sponge “Negombata magnifica (Nm)" and tube-sponge “Callyspongia siphonella (Cs)" were collected during summer 2020 from the Gulf of Aqaba (Red Sea, Egypt). Each sponge macerated with methylene chloride (CH₂Cl₂), ethyl acetate (C₄H₈O₂), acetone (C₃H₆O), and chloroform (CHCl₃) separately into four different crude extracts for each sponge species and eight extracts as a total for both marine species, where each extract was in vitro assessed for its antiproliferative and proapoptotic activity in HepG-2, MCF7, and Caco-2 cancer cell lines. Cs-CH₂Cl₂, Cs-C₄H₈O₂, Cs-C₃H₆O, Cs-CHCl₃, Nm-CH₂Cl₂, Nm-C₄H₈O₂, Nm-C₃H₆O, and Nm-CHCl₃, each in a dose-dependent manner inhibited the growth of HepG2 cancer cells within IC₅₀ values 17.53, 11.18, 9.97, 19.21, 9.14, 10.94, 8.78, and 7.23 μg/ml, respectively, MCF-7 cancer cells within IC₅₀ values of  19.48, 15.34, 11.76, 13.62, 7.65, 6.18, 11.82, and 8.26 μg/ml, respectively, and Caco-2 cancer cells within IC₅₀ values of  10.17, 14.87, 18.35, 17.12, 12.67, 9.27, 8.37, and 10.68 μg/ml, respectively.  In addition, all extracts were found to induce apoptosis in HepG2, MCF-7, and Caco-2 cancer cells via an increase of proapoptotic protein Bax and caspase-3 and decrease of anti-apoptotic protein Bcl-2. Current data introducing multiple extracts from two marine sponges as promising sources for cancer therapeutic agent(s) to be further developed for cancer control outcome.