Bone regeneration is a clinical challenge that requires multiple approaches. Sometimes, it also includes the development of new osteogenic and antibacterial biomaterials to treat the occurrence of possible infection processes derived from surgery. This study evaluates the antibacterial properties of meso-macroporous scaffolds coated with gelatin and based on a bioactive glass and after being doped with 4% ZnO (4ZN-GE) and loaded with saturated and minimally inhibitory concentrations of one of the antibiotics levofloxacin (LEVO), vancomycin (VANCO), rifampicin (RIFAM) or gentamicin (GENTA). After the physicochemical characterization of the materials, inorganic ion and antibiotic release studies were performed from the scaffolds. In addition, molecular modeling allowed the determination of electrostatic potential density maps and hydrogen bonds of the antibiotics and the glass matrix. In vitro antibacterial studies (in plankton, inhibition halos and biofilm destruction) with S. aureus and E. coli as model bacteria showed a synergistic effect of zinc ions and antibiotics. The effect was especially noticeable in planktonic cultures of S. aureus with 4ZN-GE scaffolds loaded with VANCO, LEVO or RIFAM and in cultures of E. coli with LEVO or GENTA. Furthermore, S. aureus biofilms were completely destroyed by 4ZN-GE scaffolds loaded with VANCO, LEVO or RIFAM and total destruction of E. coli biofilm was achieved with 4ZN-GE scaffolds loaded with GENTA or LEVO. This approach could be an important step in the fight against microbial resistance and provide much needed options for the treatment of bone infection.