Curcumin, an active component of turmeric, possesses different protective functions due to its anti-inflammatory, anti-oxidative and immunomodulatory activities. Curcumin's medicinal use is restricted as a result of low solubility, instability, poor bioavailability and rapid metabolism. Nanocurcumin is an enhanced form with higher tissue distribution, improved internalization and reduced systemic elimination than curcumin. Cyclophosphamide (CP), the anticancer alkylating agent, is proved to be useful for managing a wide range of cancers. Its use is limited due to harmful effects including the induction of both oxidative stress and immunosuppression. The present study evaluated the immuno-enhancement and protective properties of nanocurcumin in an immunosuppressed rat model. The experimental rats were divided into four groups (control, immunosuppressed, treated and protected) of ten rats each. Both treatment and protection trials of immunosuppressed rats with nanocurcumin significantly increased indices of spleen (119.83 and 128.61%) and liver (104.95 and 109.74%), respectively as well as the levels of immunoglobulins (IgG, 148.85 and 197.62% and IgM, 144.09% and 211.51%, respectively) beside the enhancement of the phagocytic activity of macrophages (122.37 and 156.16% respectively), in comparison with immunosuppressed rats. Both approaches down-regulated the proinflammatory cytokines comprising TNF-α (15.91 and 13.23%, respectively) and IL-1β (74.22 and 36.98%, respectively), while they upregulated the anti-inflammatory cytokines (IL-10, 130.59 and 184.68%, respectively) in splenic expression. In hepatic mRNA expression of TNF-α, both treatment and protection approaches significantly down-regulated their transcriptional level (19.17 and 46.38%, respectively), but no significant variations were reported in IL-1β expression (100.12 and 103.42%, respectively), whereas both approaches significantly up-regulated IL-10 (170.13 and 264.51%, respectively). Also, nanocurcumin restored the integrity of DNA in hepatic tissue. The protected group had more ameliorative effects than the one being treated. It could be concluded that nanocurcumin has a potential or even a vital protective activity against immunodepression in CP administered rats and could be used as an immunomodulatory agent.