Intrinsic point defects under lattice strain play a pivotal role in determining the optoelectronic performance of perovskite solar cells. Using the first-principles method, the effects of uniaxial and volumetric strain on the formation energies of common defects in γ-CsPbI3 were investigated. The results reveal that tensile strain enhances the formation energy of vacancy defects, including VI and VPb, while the larger volumetric compressive strain triggers the spontaneous generation of VPb and VCs. Pb–I–Pb bond angles and the tilt of PbI6 octahedra are closely correlated with the formation energy of defects. An increased octahedral tilt reduces the lattice symmetry, which in turn leads to a decrease in the defect formation energy. In an iodine-rich chemical environment commonly utilized in the perovskite synthesis, defects demonstrate diminished tolerance to strain, leading to a marked change in the formation energy at minimal strain levels. These findings provide a deeper understanding of uniaxial and volumetric strain on perovskites, demonstrating a strain-based strategy to improve the long-term stability and photovoltaic efficiency of perovskite solar cells.