Cnidoscolus aconitifolius (CA) and Porophyllum ruderale (PR) are representative edible plants that are a traditional food source in Mexico. This research aimed to analyze the phytochemical composition and untargeted metabolomics analysis of CA and PR and evaluate their antiproliferative effect in vitro. The phytochemical composition (UPLC-DAD-QToF/MS-ESI) identified up to 38 polyphenols and selected organic acids that were clustered by the untargeted metabolomics in functional activities linked to indolizidines, pyridines, and organic acids. Compared with PR, CA displayed a higher reduction in the metabolic activity of human SW480 colon adenocarcinoma cells (LC50: 10.65 mg/mL), and both extracts increased the total apoptotic cells and arrested cell cycle at G0/G1 phase. PR increased mRNA Apc gene expression, whereas both extracts reduced mRNA Kras expression. Rutin/epigallocatechin gallate displayed the highest affinity to APC and K-RAS proteins in silico. Further research is needed to experiment on other cell lines. Results suggested that CA and PR are polyphenol-rich plant sources exhibiting antiproliferative effects in vitro.