A new series of 4‐aryl‐4H‐chromenes bearing a 5‐arylisoxazol‐3‐yl moiety at the C‐4 position were prepared as potential anticancer agents. The in vitro cytotoxic activity of the synthesized compounds was investigated against a panel of tumor cell lines including MCF‐7 (breast cancer), KB (nasopharyngeal epidermoid carcinoma), Hep‐G2 (liver carcinoma), MDA‐MB‐231 (breast cancer), and SKNMC (human neuroblastoma) using the MTT colorimetric assay. Doxorubicin, a well‐known anticancer drug, was used as positive standard drug. Among the synthesized compounds, the 5‐(3‐methylphenyl)isoxazol‐3‐yl analog (7j) showed the most potent cytotoxic activity against all five human tumor cell lines.