The aim of this study was to investigate the mechanisms involved in the immunomodulatory effects of Morinda citrifolia L. (noni) in vitro and in vivo in mice. In vitro, Tahitian Noni Juice (TNJ) and Noni fruit juice concentrates (NFJC) (1, 5mg/mL) potently activate cannabinoid 2 (CB2), but inhibit cannabinoid 1 (CB1) receptors in a concentration-dependant manner. In vivo, oral administration of TNJ ad libitum for 16 days decreased the production of IL-4, but increased the production of IFN-gamma. These results suggest that noni modulates the immune system via activating of the CB2 receptors, and suppressing of the IL-4, but increasing the production of IFN-gamma cytokines. It may also exert beneficial immunomodulation effects in conditions involving inadequate immune responses.