This study sought to assess the leaf extracts of matoa (Pometia pinnata) and pulasan (Nephelium ramboutan-ake) for antimicrobial, antifungal, antioxidant, and cytotoxic activities, besides phytochemical content. Four extracts (hexane, ethyl acetate, ethanol, and water) were obtained from each plant via sequential extraction. The antimicrobial activities were evaluated using colorimetric broth microdilution methods. The antioxidant activities were studied using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging and ferric-reducing antioxidant power (FRAP) assays. The cytotoxicity was examined using mouse fibroblasts NIH/3T3 while the phytochemical content was detected using various chemical tests. Among the extracts, only the water extract of matoa and ethyl acetate extract of pulasan exerted bactericidal effects on Bacillus cereus (minimum bactericidal concentration (MBC): 0.63 mg/mL) and Staphylococcus aureus (MBC: 1.25 mg/mL), respectively. In contrast, all extracts, except hexane extract, of both plants exhibited fungicidal effects with minimum fungicidal concentrations of 0.31-1.25 mg/mL. All extracts of matoa leaves displayed higher DPPH radical scavenging activity and FRAP than the extracts of pulasan leaves. Notably, the water extract of matoa showed the lowest half-maximal inhibitory concentration (IC50) value of 9.88 ± 1.70 µg/mL and the highest FRAP value of 6.11 ± 0.51 mmol Fe2+ equivalent/g extract (n=3). These antioxidant activities were significantly correlated (p<0.01) with the amounts of phenolic compounds in the extracts. All extracts of both plants, except water extracts, showed significant toxicities (p<0.05) towards NIH/3T3 cells. Alkaloids, terpenoids, saponins, and glycosides were detected in the leaves of both plants. The matoa and pulasan leaves contained bioactive compounds with antibacterial, antifungal, and antioxidant activities.