Molecular engineering design is a productive atomic-scale strategy to optimize crystal structure and develop new functional materials. Herein, the first lead/tin fluorooxoborates, MB2O3F2 (M = Pb, Sn), were rationally designed by employing the nonlinear optical crystal Sr2Be2B2O7 (SBBO) as a parent model. Compared with the rigid [Be6B6O15]∞ double layers in SBBO, MB2O3F2 have flexible two-dimensional [B6O12F6]∞ single layer, which not only keeps the NLO-favorable layered structure but also overcomes the structural instability issues of SBBO. Both compounds exhibited desired short UV cutoff edge. Interestingly, MB2O3F2 exhibit widely divergent second harmonic responses, although they are isostructural and both contain stereochemically active lone-pair cations. Our first-principles calculations revealed that the SHG difference is mainly attributed to the different anisotropies of Pb and Sn SHG-active orbitals, which make constructive and destructive contributions to the SHG effects in PbB2O3F2 and SnB2O3F2, respectively.