A series of (naphthalen-1-yloxy)-acetic acid hydrazides (1–36) was synthesized and screened, in vitro, for antibacterial, antifungal, and antiviral activities. The results of antiviral activity showed that none of the tested compounds was active against viruses at subtoxic concentrations. Further, the antimicrobial screening results demonstrated that compounds having 3,4,5-trimethoxy benzaldehyde (18), o-Br, p-CN (31), and m-NO2 acetophenone (32) substituents were the most active ones against tested strains. QSAR investigations revealed that multi-target QSAR models were effective in describing the antimicrobial activity.