Perylenequinonoid natural products are a class of photosensitizers (PSs) that exhibit high reactive oxygen species (ROS) generation and excellent activity for Type I/Type II dual photodynamic therapy. However, their limited activity against gram‐negative bacteria and poor water solubility significantly restrict their potential in broad‐spectrum photodynamic antimicrobial therapy (PDAT). Herein, a general approach to overcome the limitations of perylenequinonoid photosensitizers (PQPSs) in PDAT by utilizing a macrocyclic supramolecular carrier is presented. Specifically, AnBox·4Cl, a water‐soluble cationic cyclophane, is identified as a universal macrocyclic host for PQPSs such as elsinochrome C, hypocrellin A, hypocrellin B, and hypericin, forming 1:1 host–guest complexes with high binding constants (≈107 m
−1) in aqueous solutions. Each AnBox·4Cl molecule carries four positive charges that promote strong binding with the membrane of gram‐negative bacteria. As a result, the AnBox·4Cl‐PQPS complexes can effectively anchor on the surfaces of gram‐negative bacteria, while the PQPSs alone cannot. In vitro and in vivo experiments demonstrate that these supramolecular PSs have excellent water solubility and high ROS generation, with broad‐spectrum PDAT effect against both gram‐negative and gram‐positive bacteria. This work paves a new path to enhance PDAT by showcasing an efficient approach to improve PQPSs’ water solubility and killing efficacy for gram‐negative bacteria.