Nonlinear optical (NLO) materials have received unprecedented attention owing to their capability of frequency conversion in the photoelectric fields. Yet, how to acquire a crystal with a noncentrosymmetric (NCS) structure is still a grand challenge for the NLO material. Herein, a new quaternary NCS oxychalcogenide, SrGeOSe2, was successfully designed and synthesized using the known centrosymmetric SrGeO3 as a maternal structure through a generic partial isovalent anion substitution (PIAS) strategy. SrGeOSe2 belongs to the NCS space group P212121 (no.19) and features a one-dimensional (1D) chain made by heteroligand GeO2Se2 asymmetric building units. Such a new compound exhibits desirable comprehensive performance, which suggests a promising IR-NLO material: type-I phase-matching feature, strong powder second-harmonic generation intensity (d ij = 1.3 × commercial AgGaS2), and giant powder laser-induced damage threshold (36 × commercial AgGaS2). Furthermore, the systematic theoretical investigations have been performed for the deep understanding of the correlation between the NCS structure and the NLO property. More importantly, this work pioneers a new molecular engineering strategy for NCS compounds that could be extended to other NLO materials.