Macrolides are widely prescribed in clinic to treat various respiratory tract infections. However, due to their inappropriate use, the prevalence of macrolide-resistant strains among clinical isolates has become a concern for public health. Therefore, novel macrolides skeleton structures against resistant pathogens are badly needed. Thus, three series of novel 15-membered 11a-azahomoclarithromycin derivatives (series A-C) with the 1, 2, 3-triazole side chain were designed and synthesized through creatively opening the ring of clarithromycin (CAM), expanding the ring properly and introducing a suitable side chain of 1, 2, 3-triazole at the C12 and C13 positions, and evaluated for their antibacterial activity. The antibacterial results indicated that compounds 38b, 38l and 38v possessed strong antibacterial activity against Staphylococcus aureus ATCC25923 (0.25 μg/mL) and Bacillus subtilis ATCC9372 (0.25 μg/mL). Furthermore, compounds 9e and 38g were found to exhibit promising potent activity (8 μg/mL) against Streptococcus pneumonia AB11 expressing the ermB and mefA genes. In addition, the determination of minimum bactericidal concentration (MBC) indicated that the most promising compounds 38b, 38l, 38v, 9e and 38g were excellent bacteriostatic agents. The bactericidal curve showed that 9e exhibited antibacterial activity through bacteriostatic mechanism. Finally, 38b, 38l and 38v were confirmed to be non-toxic to MCF-7 breast cancer cells up to a concentration of 32 μg/mL in preliminary cytotoxicity assay. In summary, 38b, 38l, 38v, 9e and 38g can be served as lead compounds to provide a new perspective for further structural optimization.