Fe-based metal-organic frameworks (MOFs) can be used for chemodynamic therapy (CDT) for tumors due to their unique Fenton-like effects and porous and biodegradable nature. The adsorption and transport of small molecule drugs by their structure has attracted much attention. Herein, MnO2@NH2-MIL101(Fe)@Ce6-F127 nanoparticles (MNMCF NPs) were synthesized using a facile solvothermal strategy. The small molecule photosensitizer Ce6 was adsorbed by MOFs to improve the biocompatibility of Ce6 and give it high bioavailability when injected intravenously. When the MNMCF NPs reached the tumor site, Fe-based MOFs exhibited Fenton-like properties, producing ˙OH and showing CDT effects. MnO2 could specifically respond to produce O2 in a tumor microenvironment, thereby improving the tumor hypoxia state and enhancing the efficacy of photodynamic therapy (PDT) by Ce6. Both the in vitro and in vivo experiments showed that the MNMCF-guided CDT/PDT combination therapy could effectively ablate tumors without the drawbacks of poor tolerability and potential long-term side effects. Therefore, the prepared MNMCF NPs can be used as promising candidates for synergistic CDT/PDT tumor therapy.