A series of 30 novel triazole/azide chalcone derivatives were synthesized by Claisen-Schmidt and Cu(I)-catalyzed cycloaddition reactions. The antiproliferative activity of each compound was evaluated against HeLa, RKO-AS45-1 and Wi-26VA4 cell lines. Terminal deoxynucleotidyl transferase dUTP nick end labeling assays indicated that compounds 4j and 5j significantly reduced the HeLa and RKO-AS45-1cell populations compared to the controls. The relative expression of the TP53 gene revealed changes in both cell lines after exposure to compounds 5j and 4j. The increased expression of the TP53 gene suggests a cellular attempt to repair DNA damage and indicates these triazole/azide chalcone derivatives as promising anticancer agents.