Cancer remains as the leading cause of death and targeted therapies are found unlikely to cure the disease, urging the development of new anticancer agents using “dirty” drugs. In recent years, chalcone derivatives have gained significant attention for their wide variety of biological activities, serving as a good “dirty” drugs candidate for the discovery of new leads. Motivated by studies that reported the promising anticancer activity of 2-hydroxy-4-methoxyacetophenone (HMA), we synthesised ten 2-hydroxy-4-methoxyacetophenone substituted chalcones (HMAC) (LY1 to LY10) by reacting HMA with different substituted benzaldehydes using Claisen-Schmidt condensation. The synthesized compounds were purified using column chromatography and characterized by using UV, IR, NMR and mass spectroscopy. Cell viability assay was employed to evaluate the in-vitro anticancer activity of synthesized compounds against four human cancer cell lines, MCF-7 and MDA-MB-231 (human breast cancer), HT29 (human colorectal cancer) and A549 (human lung cancer) in comparison with doxorubicin as positive control. Among ten synthesized compounds, three compounds namely LY-2, LY-8 and LY-10 exhibited potent inhibition against MCF-7, HT29 and A549 cancer cell lines with IC₅₀ values ranged from 4.61 to 9 µM. More interestingly, these compounds demonstrated low toxicity on non-cancerous human dermal fibroblast cells with IC₅₀ values more than 20 mM. The active compounds from current study could be considered as lead molecules for further studies on their potential chemotherapeutic properties in suppressing cancer cells.