A series of pyrazolo[1,5-a]pyridine-3-carboxamide (PPA) derivatives bearing diaryl side chain was designed and synthesized as new antituberculosis agents, aiming to improve the efficacy toward drug resistant Mycobacterium tuberculosis (Mtb) strains. Most of the substituted diphenyl and heterodiaryl PPAs exhibited excellent in vitro potency against the drug susceptive H37Rv strain (MIC < 0.002-0.381 μg/mL) and drug resistant Mtb strains (INH-resistant (rINH), MIC < 0.002-0.465 μg/mL; RMP-resistant (rRMP), MIC < 0.002-0.004 μg/mL). Noticeably, some compounds also showed very low cytotoxicity against Vero cells. Further, compound 6j displayed good pharmacokinetic profiles with oral bioavailability (F) of 41% and significantly reduced the bacterial burden in an autoluminescent H37Ra infected mouse model.