The discovery of camptothecin and its analogs was the major breakthrough through which ‘‘indolizine moiety’’ came into limelight. A novel compounds, 2-phenylindolizine acetamide derivatives (8a-8k) has been synthesized by the reaction of 2-oxo-2-(2-phenylindolizin-3-yl)acetyl chloride (6) with different aromatic compounds (7a-7k) in presence of triethylamine in Dichloromethane (DCM). The synthesis and screened for their antimicrobial activities of novel class of 2-phenylindolizin acetamide scaffolds are described by variation in therapeutic effects of parent molecule. Result revealed that the target compounds 8b, 8a and 8f exhibited a remarkable increase of antimicrobial activity against than reference compound ampicillin, fluconazole against in three medically relevant organisms like Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa is observed. Further, 8j and 8d showed better activity against antifungal strains Candida albicans, Aspergillus flavus and Aspergillus fumigates.