5-Lipoxygenase-activating protein (FLAP) is a regulator of cellular leukotriene biosynthesis, which governs the transfer of arachidonic acid (AA) to 5-lipoxygenase for efficient metabolism. Here, the synthesis and FLAP-antagonistic potential of fast synthetically accessible 1,2,4-triazole derivatives based on a previously discovered virtual screening hit compound is described. Our findings reveal that simple structural variations on 4,5-diaryl moieties and the 3-thioether side chain of the 1,2,4-triazole scaffold markedly influence the inhibitory potential, highlighting the significant chemical features necessary for FLAP antagonism. Comprehensive metabololipidomics analysis in activated FLAP-expressing human innate immune cells and human whole blood showed that the most potent analogue 6x selectively suppressed leukotriene B4 formation evoked by bacterial exotoxins without affecting other branches of the AA pathway. Taken together, the 1,2,4-triazole scaffold is a novel chemical platform for the development of more potent FLAP antagonists, which warrants further exploration for their potential as a new class of anti-inflammatory agents.