2D Ruddlesden-Popper perovskites have become emerging photovoltaic materials due to their intrinsic structure stability. Here, a concept of "quantum confinement breaking" in 2D perovskites is proposed using organic semiconductor spacers with suitable energy levels based on theoretical calculation and experimental results. An interesting finding is that there is intensive orbital coupling between the bithiophenemethylammonium (BThMA) spacer and adjacent inorganic layers in (BThMA)(2)PbI4, resulting in the breaking of the multiple quantum well structure. In comparison, no orbital interactions exist in (BPhMA)(2)PbI4 due to the wide bandgap of the biphenemethylammonium (BPhMA) spacer. Benefitting from the improved film quality, increased dielectric constant, and reduced binding energy, the (BThMA)(2)MA(n)(-1)Pb(n)I(3)(n)(+1) (n = 5) perovskite-based device displays an outstanding power conversion efficiency (PCE) of 18.05%, which is much higher than that of the BPhMA-based device (PCE = 12.69%) and among the best efficiency in 2D PSCs based on long conjugated spacers. The results provide an important implication for the effects of orbital interactions between organic semiconductor spacers and the adjacent [PbI6](4-) octahedron layer on the performance of 2D perovskite solar cells and other optoelectronic devices.