A facile and convenient synthesis of new pyridazines suitable for use as antimicrobial agents was reported. The hydrazide intermediate was coupled with various benzaldehydes and/or acetophenones and cyclized instantaneously to afford target pyridazine derivatives. The structures of new pyridazines were confirmed by IR, 1H- and 13C-NMR, elemental analysis in addition to representative LC/MS. Antimicrobial activity was screened against 10 bacterial and fungal strains. The new pyridazines showed strong to very strong antibacterial activity against Gram-negative (GNB) bacteria, while none of them showed significant antifungal activity at the same concentration range. Chloro derivatives exhibited the highest antibacterial activity with MICs (0.892–3.744 μg/mL) lower than that of chloramphenicol (2.019–8.078 μg/mL) against E. coli, P. aeruginosa, and S. marcescens. Prediction of ADME parameters, pharmacokinetics, and substrate promiscuity revealed that these new pyridazines could be promising drug candidates. Cytotoxic studies on rat hepatocytes showed how much safe these new pyridazines on living organisms (IC50>64 μg/mL). MOE docking studies showed a good overlay of these new pyridazines with co-crystallized ligand within an E. coli DNA gyrase subunit B active sites (4KFG).