(1) Background: Manihot esculenta, cassava, is an essential food crop for human consumption in many parts of the world. Besides the wide use of its roots, cassava leaves have been used locally as green vegetables and for medicinal purposes. However, nutritional health data regarding cassava leaves is limited, therefore we investigated its composition and associated potential bioactivity interest for human health. (2) Methods: Cassava leaf bioactivity investigations focused on antioxidant properties (free radical scavenging) in association with immunomodulatory activities on inflammatory murine macrophages to measure the impact of cassava extract on the production of pro-inflammatory cytokines such as Interleukin-6, Tumor Necrosis Factor alpha, Monocyte Chemoattractant Protein-1, Prostaglandin-E2 and mediators such as nitric oxide. (3) Results: Antioxidant and immunomodulatory bioactivities were significant, with a concentration-dependent inhibition of cytokines production by inflammatory macrophages; (4) Conclusions: Taken together, our results tend to suggest that Manihot esculenta leaves might be underrated regarding the potential nutrition-health interest of this vegetal matrix for both human nutrition and prophylaxis of metabolic disease with underlying low grade inflammation status.