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Photodynamic therapy (PDT) often suffers from the exacerbated tumor hypoxia and the heterogeneous distribution of photosensitizers, leading to an inefficient ROS productivity and availability. In this work, a mitochondria targeted O2economizer (designated as Mito‐OxE) is developed to improve PDT efficiency by alleviating tumor hypoxia and enhancing the subcellular localization of photosensitizers. Specifically, the photosensitizer of protoporphyrin IX (PpIX) is modified with the hydrophilic polyethylene glycol and the lipophilic cation of triphenylphosphine (TPP) to fabricate the biocompatible mitochondria targeted photosensitizers (designated as Mito‐PSs). And Mito‐OxE is prepared by using Mito‐PSs to load the mitochondrial oxidative phosphorylation inhibitors of atovaquone (ATO). Benefiting from the targeting capability of TPP, Mito‐OxE can selectively accumulate in mitochondria after cellular uptake. Subsequently, the mitochondrial respiration would be suppressed to with the participation of ATO, resulting in a local hypoxia mitigation for enhanced PDT. Compared with Mito‐PSs, Mito‐OxE maximizes the therapeutic effect against hypoxic tumors under light irradiation. This design of mitochondria targeted O2economizer would advance the development of targeted drug delivery system for effective PDT regardless of hypoxic microenvironment. A mitochondria targeted O2economizer (designated as Mito‐OxE) is developed for enhanced photodynamic therapy by alleviating tumor hypoxia and improving the subcellular localization of photosensitizers, which shows an overwhelming superiority for tumor suppression regardless of the hypoxic microenvironment.