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This study aimed to explore the pharmacokinetics (PK) and safety of oral (PO) and intravenous (IV) lefamulin in healthy Chinese subjects and to evaluate the efficacy of the intravenous administration regimen using pharmacokinetic/pharmacodynamic (PK/PD) analysis. This study was a randomized, open-label, single- and multiple-dose, intravenous and oral administration study. PK parameters were calculated, and the probability of target attainment (PTA) and the cumulative fraction of response (CFR) after IV administration of lefamulin 150 mg 1 h q12 h were analyzed with Monte Carlo simulations. Lefamulin exhibited extensive distribution. The mean steady-state AUC_{0–24 h} of 150 mg lefamulin IV and 600 mg lefamulin PO were 10.03 and 13.96 μg·h/mL, respectively. For <i>Streptococcus pneumoniae</i> and <i>Staphylococcus aureus</i>, based on the free-drug AUC over MIC ratio (<i>f</i>AUC/MIC) target of 1-log₁₀ cfu reduction, the PK/PD breakpoints were 0.25 and 0.125 mg/L, respectively. The CFR was over 90% for both types of strains with 95% protein binding rate, suggesting that the regimen was microbiologically effective. Lefamulin was safe and well-tolerated. The PK of lefamulin in healthy Chinese subjects were consistent with that in foreign countries. Lefamulin demonstrated the microbiological effectiveness against <i>Streptococcus pneumoniae</i> and <i>Staphylococcus aureus</i>.