Infectious diseases caused by pathogenic microorganisms are a significant burden on public health and the economic stability of societies all over the world. The appearance of drug-resistant bacteria has severely blocked the effectiveness of conventional antibiotics. Therefore, developing novel antibiotic-free strategies to combat bacteria holds huge potential for maximizing validity and minimizing the risk of enhancing bacterial resistance. Herein, a cypate-loaded hollow mesoporous Prussian blue nanoparticles (Cy-HMPBs) was built to achieve the PDT/PTT synergistic antimicrobial therapy. The carbomer hydrogel (CH) was combined with the Cy-HMPBs to form a nanoparticle/hydrogel therapeutic system (Cy-HMPBs/CH) to reach the goal of local delivery of antimicrobial cargo. The low concentration of Cy-HMPBs/CH receives over 99% of antimicrobial ability against Escherichia coli and Staphylococcus aureus upon near-infrared (NIR) irradiation. More importantly, Cy-HMPBs/CH has favorable biocompatibility and can play therapeutic effects only after laser irradiation, indicating the on-demand therapy at the targeted region to avert side effects on healthy tissue. This study provides ideas for the design of an antibiotic-free antimicrobial strategy against infectious diseases.