This work reports the synthesis and characterization of new heterocyclic chalcone derivatives 3(a–j) and in vitro biological evaluation for antiproliferative, antioxidant, antibacterial, antifungal, and antiviral properties. The antiproliferative efficacy and LC50 of the compounds against HepG2 cell lines were determined. The LC50 for 3d was found to be 8 lg/mL. All the compounds exhibited moderate DPPH scavenging activity and moderate to good antimicrobial activity against tested bacterial and fungal strains. Further, the compounds at their respective maximum non-toxic concentrations did not inhibit DNA viruses like buffalopox, camelpox, and goatpox.