The rational synthesis of high-performance inorganic two-dimensional (2D) nonlinear optical (NLO) crystals remains challenging because wide bandgaps, large birefringence, and strong second-harmonic generation (SHG) responses are difficult to optimize simultaneously. Here, we introduce retrosynthetic crystal topological chemistry (RCTC) as a predictive, topology-driven strategy for designing advanced 2D optical materials. Guided by this approach, five new inorganic layered crystals were synthesized as designed. Among them, (NH4)As2O3Br exhibits outstanding optical performance arising from densely packed and highly ordered [As2O3]∞ layers composed of [AsO3] units, delivering a large birefringence of 0.24 at 546 nm and, to the best of our knowledge, the strongest SHG response reported for solar-blind ultraviolet NLO materials (23.3 × KDP at 1064 nm). Theoretical calculations reveal that this exceptional performance originates from the high density and cooperative alignment of stereochemically active lone-pair-rich anionic groups, establishing RCTC as a versatile framework for designing next-generation 2D functional photonic materials.