Here we report a new synthetic protocol based on Microwave- Assisted Synthesis (MAS) for the preparation in higher yields of zinc and copper MOFs based on different bis(pyrazolyl)-tagged ligands ([M(BPZ)]n where M = Zn(II), Cu(II), H2BPZ = 4,4′-bipyrazole, [M(BPZ-NH2)]n where M = Zn(II), Cu(II); H2BPZ-NH2 = 3-amino-4,4’-bipyrazole, and [Mx(Me4BPZPh)] where M = Zn(II), x = 1; Cu(II), x = 2; H2Me4BPZPh = bis-4′-(3′,5′-dimethyl)- pyrazolylbenzene) and a detailed study of their antibacterial activity, tested against Gram-negative (E. coli) and Gram-positive (S. aureus) bacteria, as representative agents of infections. The results show that all MOFs exert a broad-spectrum activity and strong efficiency in bacterial growth inhibition, with a mechanism of action based on surface contact of MOFs particles with bacterial cells through the so-called “chelation effect” and reactive oxygen species (ROS) generation, without a significant release of Zn(II) and Cu(II) ions. In addition, morphological changes were elucidated by using scanning electron microscope (SEM) and bacterial cell damage was further confirmed by confocal laser scanning microscopy (CLSM) test.