PURPOSE: This study reports the synthesis of surface-modified chitosan (CS) coated with reduced graphene oxide/nickel oxide (rGO/NiO) as a multifunctional drug carrier with anti-microbial, target-specific, and stimuli-responsive capacities. CS, rGO, and NiO nanoparticles are selected due to their pH-responsiveness, large surface area, and ROS generating-capacity, respectively. METHODS: The CS/rGO/NiO nanocomposites (NCs) are synthesized using a solvothermal approach. Glutaraldehyde is used to crosslink CS and rGO/NiO to enhance the stability of the NCs. Structural properties, magnetic properties, antimicrobial activity, drug release sustainability and toxicity of the NCs are evaluated. RESULTS: The NCs show good biocompatibility, excellent magnetic properties, good target specificity, and remarkable cell growth inhibitory effects. The release of doxorubicin (DOX) from the drug-loaded NCs at pH 5.0 (~98.6%) is much higher than that at pH 7.4 (~9.6%). Furthermore, the NCs inhibit the growth of A549 and MCF7 cells, causing the viability of A549 and MCF7 to drop to 12.3% and 7.1%, respectively. By using zebrafish embryos as a model, no detectable change is observed in the survival rate of the embryos after NC treatment. CONCLUSION: The NCs exhibit multifunctional, target-specific, and pH-responsive characteristics. These properties make the NCs a promising candidate for use in drug delivery applications.