Cancer remains a significant global health challenge, necessitating ongoing efforts to develop effective anticancer medications. However, conventional drug discovery methods are costly, time-consuming, and have a negative impact on the environment. To address these issues, sustainable drug discovery approaches are being developed to minimize waste and promote eco-friendly practices. Furthermore, natural products from plant sources continue to be explored for their potential as anticancer agents. Numerous studies have highlighted the involvement of the nonsense-mediated decay (NMD) pathway, in the tumorigenesis process in humans. This study aims to explore the potential of small molecules of plant origin, known as phytomolecules, in modulating the NMD pathway's function through a molecular docking approach, followed by in silico ADME analysis. We conducted molecular docking studies of fifty phytomolecules against the human NMD factor Up-frameshift3B (UPF3B) protein. Based on the binding energy score, ten molecules with lowest score were selected for further ADME analysis. Docking results and in silico ADME analysis shows that three compounds Eriocalyxin B, Oridonin and Diosquinone could act as potential inhibitors of the human UPF3B protein and also modulate NMD pathway. The potential impact of these three compounds can be evaluated more thoroughly by employing both in vitro and in vivo methods in the development of innovative cancer treatments.