Hypoxia in the tumor microenvironment (TME) is a major barrier to photodynamic cancer therapy (PCT) that entails oxygen-dependent cell killing. TME-responsive manganese dioxide (MnO2) nanoparticles have been used to alleviate hypoxia as well as improve the efficacy of PCT. However, many types of MnO2 nanoparticles do not have sufficient colloidal dispersity and stability as well as tumor targeting ability. To solve these problems, we developed a novel well-dispersible, tumor targetable-, TME-responsive-, and hypoxia alleviating-MnO2 nano-photosensitizer through the reaction of folate-polyethylene glycol-tetraethylenepentamine-chlorin e6 (Ce6) (FAPTEC) with Mn2+ under alkaline pH conditions to produce FAPTEC/MnO2 nanoparticles. The prepared FAPTEC/MnO2 nanoparticles exhibited good colloidal dispersity and stability under biological conditions, and they significantly increased oxygen production in situ following their degradation in the hypoxic TME, leading to enhancing singlet oxygen generation after laser irradiation. Moreover, after folate receptor-mediated cellular uptake, cytocompatible FAPTEC/MnO2 nanoparticles effectively alleviated hypoxia inside 4T1 cells with high hydrogen peroxide production under hypoxic conditions. Importantly, they also exerted more potent phototherapeutic effects under normoxic and even hypoxic conditions after laser irradiation compared to other photosensitizers (free Ce6 and FAPTEC). Therefore, our results suggest that FAPTEC/MnO2 nanoparticles provide promising nano-photosensitization for enhancing hypoxia alleviation-triggered phototherapeutic effects on hypoxic tumor cells.