Objective: To compare the protective effects of chitosan-trypolyphosphate (CS-TPP) nanoparticle conjugated chloroquine(CQ) with effect of CQ alone on the reversal of splenic damages and induction of apoptosis. Methods: Different researches have been carried out to explore the potential role of chitosan based drug delivery system against parasitic diseases. After successive Plasmodium berghei NK65 parasiste infection by intraperitoneal injection in Swiss mice and subsequent parasite development, the ROS generation, anti-apoptotic and pro apoptotic protein levels in spleen were measured. To analyze caspases, flow cytometry study was performed with annexin V-FITC and with PI staining. Results: The results revealed that ROS mediated caspase 3 and 9 activation and the induction of apoptosis occurred during the parasitic infection. However, CS-TPP conjugated CQ was relatively better in reversing the splenic damage compared with similar effects of CQ alone. Conclusions: This study indicates that Plasmodium berghei NK65 induces apoptosis in the spleen. The study further shows that CS-TPP nanoparticles conjugation with CQ have positive influence on the recovery of damaged host's system towards maintenance of normal homeostasis, and this is shown to be selective to CS-TPP conjugated CQ treated animals only.