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Novel quinazolinone‐triazole hybrid heterocycles were identified as cytotoxic agents to inhibit glioblastoma cell proliferation. These compounds were synthesized using click reaction by building a triazole linker on quinazolinone and tested for cytotoxicity on C6 glioma cell lines, a facsimile of glioblastoma multiforme. Few of these series significantly reduced the proliferation of cell lines with IC508–15 μM and may act as fetching leads for glioblastoma therapies. The binding affinity and ligand‐receptor interaction between hybrids and rat thymidylate synthase were investigated using molecular docking techniques. A new series of quinazolin‐4(3H)‐ones tethered with 1,2,3‐triazolyl moiety as drug leads or drug intermediates against glioblastoma were developed. The target hybrid molecules were designed to attain better activity and selectivity towards cancer cells by introducing the lipophilic methoxybenzene moiety as a linker between quinazolin‐4 (3H)‐one and 1,2,3‐triazole scaffolds.