Curcumin (CU) is a bioactive compound extracted from turmeric and has various advantages. However, the benefit of CU is limited by its low water solubility (11 ng/mL). This research aimed to fabricate a water-soluble CU nano-formulation with chitooligosaccharides (COS) and pluronic F-68 (PF) utilizing the polymeric micelle method. The optimized curcumin-loaded chitooligosaccharides/pluronic F-68 micelles (COSPFCU) exhibited high encapsulation efficiency and loading capacity (75.57 ± 2.35% and 10.32 ± 0.59%, respectively). The hydrodynamic diameter of lyophilized COSPFCU was 73.89 ± 11.69 nm with a polydispersity index below 0.3. The COSPFCU could be completely redispersed in water and showed high DPPH scavenging ability. Meanwhile, COSPFCU could significantly reduce the cytotoxicity of the RAW 264.7 cells compared to native CU. Furthermore, COSPFCU improved the inhibition of NO release activity at 72.83 ± 2.37% but 33.20 ± 3.41% for the CU, with a low cytotoxicity concentration in the RAW 264.7 cells.