ABSTRACT A new series of spiro‐heterocycles derived from pyrazole–indenoquinoxaline scaffolds 4a–n and 5a–m was designed and synthesized via one‐pot multi‐component reaction‐based a [3 + 2] cycloaddition reaction (32CA). The Molecular Electron Density Theory (MEDT) has been used to theoretically study the 32CA reaction between azomethine ylide (AY) 6a and the electrophilic ethylene 1a . This 32CA reaction, which proceeds via a two‐stage one‐step mechanism, yields the spiro‐cycloadduct 4a with high ortho/endo selectivity. The newly pyrazole‐tethered indenoquinoxaline‐based spiro‐heterocycles 4a–n and 5a–m were evaluated for their anticancer activities against MCF‐7 and HepG‐2 cancer cell lines. These compounds were targeted as dual EGFR/VEGFR‐2 kinase inhibitors. Interestingly, 4l exhibited the most substantial inhibitory effect, with a potent effect on HepG2 cells (1.35 µM) and poor cytotoxicity on MCF‐7 (≥50 µM). However, compound 4f displayed a unique antiproliferative potency on HepG2 cells (7.9 µM) and a promising cytotoxicity in MCF‐7 (13.5 µM), compared to sorafenib with IC 50 values of 2.1 and 2.3 µM against MCF‐7 and HepG‐2 cancer cells. Compound 4f treatment induced total apoptosis in the HepG2 cancer cells by 36.3‐fold, arresting the cell proliferation at the G1‐phase by 83.4%. Accordingly, compounds 4l and 4f exhibited target‐oriented chemotherapeutic activity against liver cancer.