Plant-based bioactive compounds, particularly kaempferol and quercetin, exhibit notable anti-inflammatory and anticancer potential. This systematic review evaluates experimental evidence on the effects of kaempferol and quercetin, in pure and isolated forms, against lung, breast, and colorectal cancers using in vitro and in vivo models. A systematic search of PubMed, Google Scholar, Taylor & Francis, and Wiley Online Library was conducted in October 2025 following PRISMA guidelines. Studies investigating pure kaempferol or quercetin in human-derived cancer cell lines and animal models were included, while clinical and combination studies were excluded. Only quercetin-based in vivo studies met eligibility criteria. Out of 377 identified records, 24 studies were included. Both compounds consistently reduced cancer cell viability, induced apoptosis. They inhibited proliferation and migration by modulating the PI3K/Akt, MAPK, NF-κB, and p53 pathways across breast, lung, and colorectal cancer cell lines. Among the included studies, 16 were in vitro, and 8 were in vivo, with predominantly low risk of bias, indicating robust methodological quality. Overall, kaempferol and quercetin demonstrate strong anticancer activity in preclinical models, highlighting their promise for cancer prevention and management. However, well-designed clinical trials are needed to confirm their potential therapeutic relevance. The online version contains supplementary material available at 10.1007/s12672-026-04901-9.