Hollow microspheres with open windows on the shells have shown significant potential in adsorption, catalysis, and drug delivery fields, owing to their low density, large interior volume, high specific surface area, and abundant availability of adsorption sites. However, creating open hollow spheres with structurally stable and entirely organic‐functionalized surfaces remains a challenge. Herein, we fabricated polysilsesquioxane open hollow spheres using trialkoxysilane containing mercaptopropyl groups under vigorous stirring, employing polystyrene microspheres as template. Various reaction parameters were explored, revealing stirring speed as the key factor influencing the morphology and openness of the microspheres. By examining the morphology of intermediate products at different reaction times, we proposed a step‐growth mechanism for microsphere formation. The resulting materials exhibited high adsorption capacity and selectivity towards Hg2+ and Pb2+, attributed to the presence of thiol groups and the open‐hollow structure. Our approach provides a robust method for producing open hollow materials with functionalized surfaces, offering potential applications in the adsorption field.