Metronidazole (MTZ) is a drug potentially used for the treatment of intestinal infections, namely, the ones caused by colorectal surgery. The traditional routes of administration decrease its local effectiveness and present off-site effects. To circumvent such limitations, herein a drug delivery system (DDS) based on MTZ-loaded nanoparticles (NPs) immobilized at the surface of electrospun fibrous meshes is proposed. MTZ at different concentrations (1, 2, 5, and 10 mg mL-1) was loaded into chitosan-sodium tripolyphosphate NPs. The MTZ loaded into NPs at the highest concentration showed a quick release in the first 12 h, followed by a gradual release. This DDS was not toxic to human colonic cells. When tested against different bacterial strains, a significant reduction of Escherichia coli and Staphylococcus aureus was observed, but no effect was found against Enterococcus faecalis. Therefore, this DDS offers high potential to locally prevent the occurrence of infections after colorectal anastomosis.