In recent years, certain amphipathic, α-helical peptides have been discovered that inhibit medically important enveloped viruses by disrupting the lipid membrane surrounding individual virus particles. Interestingly, only a small subset of amphipathic, α-helical peptides demonstrate inhibitory activity, and there is broad interest in understanding how the structures of these peptides contribute to functional activity against lipid membranes. To address this question, herein, we employed multiple surface-sensitive measurement techniques along with computational simulations in order to investigate how AH and C5A peptides, two of the most biologically active peptides in this class, interact with model lipid membranes while gaining insight into membrane-induced peptide conformational changes. Circular dichroism spectroscopy experiments revealed that both AH and C5A peptides undergo pronounced coil-to-helix transitions in the presence of lipid membrane environments, and the C5A conformational change was the largest. Time-lapsed fluorescence microscopy measurements were conducted to monitor the interaction of peptides with arrays of tethered, individual lipid vesicles and showed that C5A potently lyses lipid vesicles indiscriminate of vesicle size at peptide concentrations as low as 10 nM whereas AH peptide preferentially lyses lipid vesicles with high membrane curvature and is less potent than C5A. These findings were complemented by electrochemical impedance spectroscopy measurements on a tethered lipid bilayer membrane platform, which indicated that C5A solubilizes lipid membranes in a manner that is distinct from how AH disrupts lipid membranes via pore formation. Computational simulations supported that the distinct membrane-interaction profiles arise from different helical folding patterns, whereby AH monomers predominantly exist as two shorter helices with a hinge in-between and C5A monomers form a single helix. Taken together, our findings demonstrate that membrane-active antiviral peptides can exhibit distinct membrane-interaction profiles that confer different degrees of targeting selectivity, and the corresponding structural insights will be useful for peptide engineering applications.