A series of pyrazolo[1,5-a]pyridine-3-carboxamide hybrids were designed and evaluated as novel anti-tubercular agents. The representative hybrid 7 exhibited promising in vitro activity against susceptive strain H37Rv and a panel of drug-resistant Mtb strains with MIC values of 0.006 μg/mL and ranged from 0.003 to 0.014 μg/mL, respectively. More importantly, the hybrid 7 also showed very low cytotoxicity, and could significantly reduce the mycobacterial burden in a mouse model infected with autoluminescent H37Ra strain, which may serve as a lead compound for further development of new anti-tubercular agents.