Herein, new Pyrrolo[3,4-d] isoxazolidines hybrid with furan were synthesized by 1,3-dipolar cycloaddition reaction of nitrone 2 with N-substituted maleimides 3a-j. The synthesized compounds were screened in vitro cytotoxic assay against four cancer cell lines namely, HeLa, HEPG-2, HCT-116 and MCF-7 using doxorubicin (DOX) as a reference using MTT assay. The results demonstrated that compounds 4b and 4j exhibited the highest antitumor activity with IC₅₀ =6.22–16.44  μM in comparable to DOX (IC₅₀ = 4.17–5.57μM). The most active hybrids 4b and 4j were further subjected to multi-targeting assays against EGFR, VEGFR-2, and Topo II. They showed good to moderate inhibitory activities. In addition, flow cytometric analysis of 4b and 4j inhibited cell population of MCF-7 cells in the S phase. Compound 4b, and 4j were further evaluated using molecular docking and dynamics simulations (20 ns) and the EGFR, TOPII, or VEGFR-2 receptor protein. All the data sets accurately predict the strongest binding affinity for the selected compounds, as evidenced by the highest free binding energy from MM/GBSA calculations and significant amino acid steric interactions. Furthermore, the RMS/RMSF/Rg/SASA dynamics parameters show the formed complexes demonstrate satisfactory stability. The ADMET properties indicate that the selected new ligands have shown a promising drug-like profile and can be considered potential candidates for future anti-cancer therapies, with perspective validating their anticancer activity by in vitro studies.