Keeping in view various pharmacological attributes of indole and coumarin derivatives, a new series of indolindione-coumarin molecular hybrids was rationally designed and synthesized. All synthesized hybrid molecules were evaluated for their antimicrobial potential against Gram-negative bacterial strains ( and ), Gram-positive bacterial strains ( and ), and four fungal strains (, , sp., and ) by using the agar gel diffusion method. Among all synthetics, compounds and were found to be the best antimicrobial agents with the minimum inhibitory concentration values of 30 and 312 μg/mL, against sp. and , respectively. The biological data revealed some interesting facts about the structure-activity relationship which state that the electronic environment on the indolinedione moiety and carbon chain length between indolinedione and triazole moieties considerably affect the antimicrobial potential of the synthesized hybrids. Various types of binding interactions of within the active site of dihydrofolate reductase were also streamlined by molecular modeling studies, which revealed the possible mechanism for potent antibacterial activity of the compound.