A series of new biaryloxazolidinone derivatives has been designed and synthesized using the combination principle and blocking metabolic site to improve their antibacterial activity and stability. Apart from the excellent antibacterial profile against S. aureus (MIC = 0.25 μg mL⁻¹), MRSA (MIC = 0.25 μg mL⁻¹), LREF (MIC = 0.031 μg mL⁻¹), VRE (MIC = 0.031 μg mL⁻¹), GBS (MIC = 0.031 μg mL⁻¹), and Spn (MIC = 0.031 μg mL⁻¹), compound 13b-6 also displayed good stability and safety, excellent rat PK profile with long half-life time (T_1/2 = 17.7 h), and moderate plasma exposure (AUC_0–t = 74.4 ng mL⁻¹).