After lifting COVID-19 restrictions, pneumonia caused by influenza A virus coinfection with Mycoplasma pneumoniae bacteria emerges as a matter of concern. Only a few reports have recently proposed natural compounds for treating the coinfection of influenza A virus and M. pneumoniae, especially resistant strains. Hence, this study demonstrated in silico investigation of two natural classes (flavan-3-ol and flavanone) that could become future inhibitors for bifunctional neuraminidase and anti-M. pneumoniae. Combining the molecular docking with basedvirtual screening strategies for over 900 ligands with neuraminidase protein of oseltamivir-resistant virus strain at H274Y mutation (PDB ID: 3CL0), 03 flavan-3-ols and 46 flavanones interacted with both the active site and the adjacent 430-cavity, and showed lower binding energies than laninamivir (- 8.1 kcal/mol). The four most suitable candidates (FL22, FN166, FN316, and ChEMBL1779463) also exhibited potential characteristics for inhibiting M. pneumoniae through some vital targets (30S Ribosome-binding factor A (PDB ID: 1PA4) and immunodominant protein P40/P90 complex (PDB ID: 6TLZ)). Furthermore, the total-synthesis strategy of ChEMBL1779463 was successfully proposed using commercial reagents and modern techniques. Our results will offer potential insights for future methods to identify biflavonoids, especially biflavanone, to simultaneously suppress the resistant strains of influenza A virus and M. pneumoniae.