Cancers are one of the leading causes of death worldwide, and in spite of the progress in anticancer drug development, it is still imperative to find novel natural medicines. Therefore, this study was aimed at the evaluation of cell cycle arrest, apoptosis, and cytotoxicity induction via Lonicera nummularifolia, Lilium ledebourii, Campsis radicans and Parthenocissus quinquefolia extracts. Each extract was treated on G292, A431, and KB cancer cell lines, which compared to the HGF-1 normal cell line. From the MTT assay, all extracts significantly enhanced the cell death rate in three cancer cell lines more than the HGF-1 line. Based on evidence from the cell cycle, MTT and apoptosis tests, the Methanolic extract of L. ledebourii bulbs exhibited a considerable efficacy on apoptosis induction in the cancer cell lines. It seems that the mode of action for L. ledebourii Methanolic extract is due to the increased BID/MAPK14 expression and the decreased MDM2/BCL2/MYC expression, which lead to activation of the p53 protein-induced apoptosis. The crude extract was separated into fractions by preparative HPLC and effective fraction was characterized by Triple-Quad LC/MS connected to the UHPLC system. Overall, the findings suggest that L. ledebourii is a promising source of bioactive compounds, which are proven natural anticancer compounds.