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The presence of <i>Staphylococcus epidermidis</i> biofilms on medical devices is a major cause of nosocomial diseases and infections. Extensive research is directed at inhibiting the formation and maturation of such biofilms. Natural plant-derived phenolic compounds have promising antimicrobial effects against drug-resistant bacteria. The anti-biofilm activity of two selected phenolic compounds (vanillin and syringic acid) was tested against three biofilm-forming methicillin-resistant <i>S. epidermidis</i> strains with different genotypes. Resazurin assay combining crystal violet staining and confocal microscopy was used for biofilm and extracellular polymer substance (EPS) inhibition tests. Effects on EPS compounds such as proteins, extracellular DNA, and polysaccharides were also examined. Combined with quantitative real-time PCR of selected <i>agr</i> quorum-sensing systems and biofilm genetic determinants, our complex analysis of vanillin and syringic acid showed similar biofilm and EPS inhibition effects on <i>S. epidermidis</i> strains, reducing biofilm formation up to 80% and EPS up to 55%, depending on the genotype of the tested strain. Natural antimicrobial agents are thus potentially useful inhibitors of biofilms.