In continuation of our endeavor towards the development of potent and effective antimicrobial agents, three series of halophenyl bis-hydrazones (14a-n, 16a-d, 17a and 17b) were synthesized and evaluated for their potential antibacterial, antifungal and antimycobacterial activities. These efforts led to the identification of five molecules 14c, 14g, 16b, 17a and 17b (MIC range from 0.12 to 7.81 μg/mL) with broad antimicrobial activity against Mycobacterium tuberculosis; Aspergillus fumigates; Gram positive bacteria, Staphylococcus aureus, Streptococcus pneumonia, and Bacillis subtilis; and Gram negative bacteria, Salmonella typhimurium, Klebsiella pneumonia, and Escherichia coli. Three of the most active compounds, 16b, 17a and 17b, were also devoid of apparent cytotoxicity to lung cancer cell line A549. Amphotericin B and ciprofloxacin were used as references for antifungal and antibacterial screening, while isoniazid and pyrazinamide were used as references for antimycobacterial activity. Furthermore, three Quantitative Structure Activity Relationship (QSAR) models were built to explore the structural requirements controlling the different activities of the prepared bis-hydrazones.