A model for predicting the anticipated second harmonic generation (SHG) activity of crystalline active pharmaceutical ingredients (APIs) was developed based on combining time-dependent Hartree−Fock calculations of the molecular building block with analytical theory for the predicted intensity from the lattice. Predicted trends agreed well overall with experimental measurements for 18 representative APIs. Inspection of the SHG images suggests that outliers from the predicted trends likely arose from the presence of trace SHG-active metastable crystal forms not considered in the predictions. The success of this relatively simple computational approach suggests a route for reliably predicting the anticipated SHG activities of API target molecules, which in turn can serve to indicate their potential compatibility with analysis by SHG.