Maltol, mostly used as a flavoring molecule, also has various potential applications as a biomedical compound. Despite its extensive use in the food industry, maltol’s antimicrobial activity was evaluated only briefly, and was suggested to be insufficient on its own. Recently, we have shown that maltol can be used in conjunction with cationic surfactant species to receive higher activity against contaminant microorganisms. In this paper, we have broadened the antimicrobial efficacy studies and evidenced maltol’s mode of action against Gram-negative, Gram-positive bacteria, and fungi. In addition, to increase its efficacy, blends of maltol and two selected cationic surfactants, dodecyl-dimethyl-ammonium chloride (DDAC) and polyquaternium 80 (P-80), were appraised for their activity. Broad efficacy studies revealed synergistic interactions between maltol and both cationic surfactants against most of the tested microorganisms. Electron microscopy images were used to evaluate the microorganisms’ morphology following treatment, pinpointing the specific cell wall damage caused by each of the compounds. Our findings indicate that maltol’s effect on the microbial cell wall can be complemented by catalytic amounts of selected cationic surfactants to enhance and extend its activity. Such a solution can be used as a broad-spectrum preservative for personal care products in cosmetic applications.