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This study was aimed at investigating the immunomodulating activities of molokhia leaf extract. To examine the immunomodulatory activities of a water-soluble molokhia (Corchorus olitorius) leaf extract (WME), nitric oxide (NO) and cytokine levels in relation to macrophage activation were estimated in a cyclophosphamide-induced murine model of immunosuppression, and a natural killer (NK) cell cytotoxicity assay was conducted. Administration of WME significantly augmented NK cell cytotoxicity against YAC-1 cells by inducing the release of granzyme B. In addition, murine peritoneal macrophages stimulated by WME produced various cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-6. The results of this study showed that WME administration (50 and 100 mg/kg) increased thymus and spleen indices, and the leukocyte count in the blood of immunosuppressed mice. These results demonstrated that WME possesses immunomodulatory activity and may represent a potential immunostimulant for enhancing human immunity.