Oxygen as one of the most critical substances in living organisms has attracted ever‐increasing attention in disease treatment, which is important in regulating metabolic activities. However, the hypoxia arising from disease is a prevalent problem, leading to observably reduced therapeutic effectiveness in photodynamic therapy, radiotherapy, sonodynamic therapy, etc. Therefore, the reversion of hypoxia becomes the basis for enhancing the disease treatment. Thanks to the development of nanotechnology, various nanomaterials with oxygen‐production capacity are explored to recover the function of oxygen in tissue, but there are still some limitations. The photosynthetic microorganisms (PSMs) are extensively applied for improving hypoxia in diseases due to their highly efficient photocatalytic oxygen production efficacy and desirable biocompatibility. In this review, the up‐to‐date research progress on therapeutic modalities of microbial‐based photosynthetic oxygenation (e.g., cancer treatment, wound healing, and tissue engineering) are summarized and highlighted. In addition, the key issue of biocompatibility/biosafety of microbial‐based treatment that is fundamental to apply in vivo is further emphasized and clarified. Finally, the present critical issues are discussed and the future evolution of microbial‐based treatment based on photosynthetic oxygenation is predicted, promoting further development and clinical applications.