Herein we describe efficient and cost-effective synthesis of azo-based and aminomethylene derivatives of cyclic β-keto sulfones, specifically, 4,4-disubstituted (E)-2-(2-phenylhydrazineylidene)dihydrothiophen-3(2H)-one 1,1-dioxides and 4,4-disubstituted (E)-2-((methylamino)methylene)dihydrothiophen-3(2H)-one 1,1-dioxides. The azo-based derivatives were prepared through the azo coupling of cyclic β-keto sulfones with aromatic diazonium acetates, in situ prepared by diazotization of appropriate substituted amino benzenes. The aminomethylene derivatives were synthesized through the condensation of cyclic β-keto sulfones with DMF-DMA followed by a transamination reaction with primary amines. The target products were obtained in good yields and their structure was unambiguously established based on NMR spectra data, X-ray diffraction study, and DFT calculations. These compounds were designed as cost-effective and multitarget biologically active compounds. Further in vitro study showed antibacterial activity against Staphylococcus aureus and cytotoxicity against the MDA-MB-231 breast cancer cell line without affecting non-malignant cells MAEC. The molecular docking study confirmed good binding affinity of the studied compounds for DHPS, crucial for the bacterial life cycle and for CLK4 and IDO1, which are the therapeutic targets in cancer treatment.