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Objective To investigate the antibacterial activity of contezolid and linezolid against common Gram-positive bacteria and to preliminarily analyze the mechanism of their inhibition of biofilm. Methods Staphylococcus aureus (S. aureus) and Enterococcus faecalis (E. faecalis) were taken as the research objects. We used the broth dilution method to determine the minimum inhibitory concentration (MIC) of contezolid and linezolid against S. aureus and E. faecalis. The growth curve was used to detect the growth of bacteria under different drug concentrations, and the formation of bacterial biofilm and the survival rate of bacteria in the biofilm were observed by crystal violet staining under the drug concentration that did not inhibit the growth of bacteria. Proteomics was used to screen the differentially expressed proteins in the biofilm of Gram-positive bacteria under the action of contezolid and linezolid. Functional annotation of gene ontology (GO), Kyoto Encylopaedia of Genes and Genomes (KEGG), and protein interaction network (PPI) was used to observe the interaction between proteins. Results Contezolid and linezolid showed broad-spectrum antibacterial activity against S. aureus and E. faecalis, and their MICs were both less than 4 µg/mL. The growth curve showed that contezolid and linezolid at 1/2 × MIC had no effect on bacterial growth. The result of crystal violet staining and the count of viable bacteria in biofilm showed that both drugs could inhibit the formation of S. aureus and E. faecalis biofilm at sub-inhibitory concentration. There were 290 and 222 differentially expressed proteins in the biofilm of Gram-positive bacteria under the action of contezolid and linezolid. The differential proteins mainly involved Rpm, rplE, SasG, Luxs, ald 1, D-alanine aminotransferase, etc. GO analysis showed that the differentially expressed proteins were mainly related to pyruvate metabolism and amino acid metabolism under the action of contezolid. The differential expression of proteins under linezolid mainly involved pyrimidine metabolism, purine metabolism, amino acid metabolism, etc. KEGG analysis showed that the differentially expressed proteins treated with contezolid mainly involved in naphthalene degradation, pyrimidine metabolism, glycolysis, and ribosome excision and repair. The differentially expressed proteins treated with linezolid mainly involved amino acid degradation, fatty acid degradation, purine metabolism, pentose, and glucose phosphate conversion. PPI analysis showed that the differentially expressed proteins under the action of two antibiotics were mainly related to ribosomes. Conclusions Contezolid and linezolid show broad-spectrum antibacterial activity and biofilm inhibition against Grampositive bacteria. These two drugs may inhibit the formation of biofilm of Gram-positive bacteria by inhibiting quorum sensing system, primary metabolism and biofilm formation related genes. [ABSTRACT FROM AUTHOR]