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Background: Histone deacetylases (HDACs) are the enzymes that catalyze the removal of the acetyl groupfrom lysine residues and regulate several biological processes. Suberoylanilide hydroxamic acid (SAHA) is a notableHDAC inhibitor that exhibited remarkable anti-proliferative efficiency by alleviating gene regulation against solid andhematologic cancers. Aim: The aim of this study was to develop new chemotherapeutic agents for breast cancer treatment, therefore, anovel series of Suberoylanilide hydroxamic acid (SAHA) analogs were investigated as anticancer agents. Methods: We designed and synthesized a novel series of analogs derived from SAHA by substituting alkyl, alkoxy,halo, and benzyl groups at different positions of the phenyl ring. The newly synthesized analogs were assessed for theircytotoxic potential against four human cancer cell lines in comparison with healthy cell lines, using several biologicalassays. Results: SAHA analogs displayed significant cytotoxic potential with IC50 values ranging from 1.6 to 19.2 μMin various tumor cell lines. Among these analogs, 2d (containing 3-chloro, 4-floro substitutions on phenyl moiety),2h (containing 3,4-di chloro substitutions on phenyl moiety), and 2j (containing 4-chloro, 3-methyl substitutionson phenyl moiety) showed significant cytotoxic potential with IC50 values ranging from 1.6 to 1.8 μM in MCF-7(breast carcinoma) cell line. More importantly, these analogs were found to be non-toxic towards healthy primaryhuman hepatocytes (PHH) and mouse fibroblast cells (NIH3T3), which represent their tumor selectivity. These analogswere further analyzed for their effect on cell migration, BrdU incorporation, Annexin V-FITC and cell cycle arrest(Sub-G1 phase). Remarkably, analogs 2d, 2h, and 2j displayed significant HDAC inhibition than the parent SAHAmolecule. Further studies also confirmed that these SAHA analogs are efficient in inducing apoptosis, as they regulatedthe expression of several proteins involved in mitochondrial or intrinsic apoptosis pathways. Findings in the ChickChorioallantoic Membrane (CAM) assay studies revealed anti-angiogenic properties of the currently described SAHAanalogs. Conclusion: From anti-proliferative study results, it is clearly evident that 3,4-substitution at the SAHA phenyl ringimproves the anti-proliferative activity of SAHA. Based on these findings, we presume that the synthesized novelSAHA analogs could be potential therapeutic agents in treating breast cancer.