Galbanic acid (GBA) is an active sesquiterpene coumarin derivative, with various medicinal benefits, including anticancer properties. However, the low solubility of GBA is the main limitation of its clinical applications. In this study, we used a nanosystem based on poly (D, l-lactide)-polyethylene glycol (PLA-PEG), for the delivery of GBA to C26 colon carcinoma cells. The physicochemical characteristics of nanoparticles (NPs) prepared by the emulsification-evaporation method were evaluated. MTT assay was used to compare the anticell proliferation of GBA and PLA-PEG-GBA against C26 cell lines. PLA-PEG-NPs with an average size of about 140 nm had an enhanced release of GBA at a pH of 5.5 compared with a pH of 7.4. Cytotoxicity studies showed that the IC of the PLA-PEG-GBA NPs (8 µM) was significantly lower than free GBA (15 µM). In the in vivo study, PLA-PEG-GBA NPs exhibited remarkable efficacy and reduced in vivo toxicity in C26 colon carcinoma tumor-bearing female BALB/c mice. To study the antiangiogenesis effect of the NPs, tumor sections were stained with an anti CD34 antibody. The results show the CD34 (+) vessels were decreased in the GBA and PLA-PEG-GBA treated mice by more than 75% and 90%, respectively. These results suggest that the encapsulation of GBA into the PLA-PEG could potentially be used for the treatment of colorectal cancer.