Molecular surface modification has been widely used to improve the stability and the power conversion efficiency of perovskite solar cells. First-principles studies have played a crucial role in the mechanism of surface modification. However, the design of surface modification molecules lacks theoretical guidelines. Herein, we studied the surface modifications of a series of typical small molecules based on first-principles calculations. The relevance of the calculated properties and experimental performance has been investigated. It was found that molecules with nitrogen-containing groups, including amino, π-conjugated N-heterocycle, and (thio)amide groups, could have strong adsorption energies, and may be suitable modifiers. Molecules such as oxygen-containing six-membered rings and 1,2,4-triazine may induce defect states. Based on our calculations, design guidelines for perovskite surface modification molecules have been proposed based on three aspects: interfacial buffering, defect avoidance, and energy level alignment. This work may shed light on the development of perovskite surface modification molecules towards higher power conversion efficiency and more stable perovskite solar cells.