Purpose <p>This study evaluates the in vitro antimicrobial activity of Corallopyronin A (CorA) against a diverse collection of <i>Staphylococcus aureus</i> and coagulase-negative staphylococci (CNS), comprising both laboratory strains and clinical isolates. The dataset includes methicillin-resistant and methicillin-susceptible strains, as well as small colony variants (SCVs), to assess its therapeutic potential in staphylococcal infections.</p> Methods <p>A total of 116 staphylococcal strains, comprising clinical isolates and laboratory strains, were subjected to minimum inhibitory concentration (MIC) testing. Minimum bactericidal concentrations (MBCs) were determined for a subset of 70 strains. Time-kill assays were conducted for five <i>S. aureus</i> strains using 4 × MIC of CorA. Additionally, checkerboard assays were performed with 11 antibiotics to evaluate potential additive or synergistic interactions.</p> Results <p>CorA demonstrated potent antimicrobial activity with MIC values ranging from 0.125 to 2&#xa0;mg/L. The MIC₉₀ was 0.5&#xa0;mg/L for <i>S. aureus</i> and 1&#xa0;mg/L for CNS. Methicillin-resistant strains exhibited significantly higher susceptibility than methicillin-sensitive strains. Time-kill assays revealed a reduction of 1.5-3 log₁₀ CFU/mL in viable counts within 24&#xa0;h. Minimum bactericidal concentration testing showed bactericidal activity in a subset of strains, occurring in 71% of CNS isolates and 34% of <i>S. aureus</i> strains, while the remaining <i>S. aureus</i> and CNS isolates displayed a bacteriostatic response. Checkerboard assays indicated additive interactions with glycopeptides, including dalbavancin and oritavancin.</p> Conclusions <p>CorA shows strong in vitro activity against a broad range of staphylococcal strains, particularly methicillin-resistant isolates. Its additive effects with clinically relevant antibiotics further support its potential in combination therapy for the treatment of resistant staphylococcal infections.</p>