Superbugs, as bacterial resistance species, resist known antibiotics. In this study, twenty novel 1,2,4-triazole-functionalized piperazine-stearic acid derivatives 6a-p were designed, synthesized, and characterized via spectroscopic analyses, evaluating their antimicrobial potential against clinically relevant bacterial and fungal strains. Notably, five derivatives (6a, 6c, 6m, 6n, and 6o) demonstrated superior antimicrobial efficacy compared to gentamicin standard, with compound 6n showing the most potent activity (MIC = 3.125 μg/mL against S. aureus). Molecular docking simulations further revealed strong binding affinities of these compounds to microbial target proteins (ΔG = -8.2 to -9.7 kcal/mol). These findings present promising antimicrobial candidates of 1,2,4-triazole-appended piperazine-stearic moiety derivatives.