Lewis base molecules are widely used to passivate structural defects in perovskites. However, the spatial compatibility between these molecules and the perovskite lattice is seldom considered. Herein, a multisite atomic‐oxygen (O) anchoring passivation strategy using 1,1,2,2‐tetra(4‐methoxyphenyl)ethene (TMPE), which contains four electronegative O atoms to selectively anchor iodine vacancies and passivate under‐coordinated Pb2+ or MA+ defects is proposed. It is found that the distance between any three O atoms in a TMPE molecule matches that of iodine ions in the lattice structure, thereby maximizing passivation effects and enhancing lattice stability. Additionally, the coordination of TMPE facilitates the formation of larger colloid sizes in the precursor solution, effectively regulating crystal growth. Due to the molecular extrusion effect, TMPE‐based anchors localize on the surface, passivating defects and mitigating nonradiative recombination. As a result, defects in MA‐based and FA‐based perovskite films are significantly reduced, achieving optimized power conversion efficiencies (PCEs) of 19.9% and 24.5%, while exhibiting exceptional stability by retaining 90% of initial PCE after 1200 h of storage without encapsulation. This single molecule‐controlled perovskite multisite anchoring strategy would help resolve lattice stability issue caused by perovskite defects, thereby paving the pathway for the development of high‐performance and highly stable perovskite solar cells.