A growing incidence of drug resistance and tumour proliferation in non-small cell lung cancer escalates the urge for potential lead molecules. The plant-derived natural compounds have played a pivotal role in potential therapeutic agents owing to its versatility and low toxicity over the past decades. In this study, we have executed an in-silico based screening of 1574 natural compounds against the β-catenin via an integrated pharmacophore approach. Further investigation revealed that Mucronulatol and 7,4'-dihydroxyhomoisoflavanone possess a higher Glide score (−4.748 and −3.943 kcal/mol), binding affinity (−44.763 and −41.883 kcal/mol) alongside drug-likeness property than the iCRT5. Moreover, these compounds are reported to have cytotoxicity against lung cancer cell lines with an IC50 value of 6.74 µM and 8.99 µM respectively. Furthermore, dynamic studies were employed to determine the structural stability and we hope that the lead molecules proposed in this study could effectively inhibit the β-catenin pathway associated with NSCLC. © 2020 Informa UK Limited, trading as Taylor & Francis Group.