Keeping in view various pharmacological attributes of curcumin, coumarin, and isatin derivatives, triazole-tethered monocarbonyl curcumin-coumarin and curcumin-isatin molecular hybrids have been synthesized and evaluated for their antibacterial potential against Gram-positive ( and ) and Gram-negative ( and ) human pathogenic bacterial strains. Among all hybrid molecules, and showed the most potent antibacterial activity with inhibition zones of 29 and 31 mm along with MIC values of 12.50 and 6.25 μg/mL, respectively. Structure-activity relationship that emerged from biological data revealed that the two-carbon alkyl chain between triazole and coumarin/isatin moiety is well tolerable for the activity. Bromo substitution at the fifth position of isatin, para-cholo substitution in the case of curcumin-isatin, and para-methoxy in the case of curcumin-coumarin hybrids on ring A of curcumin are most suitable groups for the antibacterial activity. Various types of binding interactions of and within the active site of dihydrofolate reductase (DHFR) of are also streamlined by molecular modeling studies, suggesting their capability in completely blocking DHFR.