We previously discovered a series of novel biaryloxazolidinone analogues bearing a hydrazone moiety with potent antibacterial activity. However, the most potent compound OB-104 exhibited undesirable chemical and metabolic instability. Herein, novel biaryloxazolidinone analogues were designed and synthesized to improve the chemical and metabolic stability. Compounds 6a-1, 6a-3, 14a-1, 14a-3 and 14a-7 showed significant antibacterial activity against the tested Gram-positive bacteria as compared to radezolid and linezolid. Further studies indicated that most of them exhibited improved water solubility and chemical stability. Compound 14a-7 had MIC values of 0.125-0.25 μg/mL against all tested Gram-positive bacteria, and showed excellent antibacterial activity against clinical isolates of antibiotic-susceptible and antibiotic-resistant bacteria. Moreover, it was stable in human liver microsome. From a safety viewpoint, it showed non-cytotoxic activity against hepatic cell and exhibited lower inhibitory activity against human MAO-A compared to linezolid. The potent antibacterial activity and all these improved drug-likeness properties and safety profile suggested that compound 14a-7 might be a promising drug candidate for further investigation.