<p>An eco-friendly TiO₂-supported ZnO (TiO₂-ZnO) heterogeneous catalyst with different ZnO contents was synthesized by following the wetness impregnation method and characterized by SEM–EDX and XRD. The catalytic performance of these TiO₂-ZnO nano-catalysts, with different ZnO ratios, was investigated for the first time in the Kabachnik–Fields reaction (one-pot three-component reaction) to produce α-aminophosphonates, whereas α-hydroxyphosphonates were produced in the two-component Pudovik reaction, both under neat reaction conditions. The results demonstrated that the TiO₂-ZnO catalyst achieved excellent yields of α-amino/hydroxyphosphonates <b>(4a-f</b> and <b>5a-f)</b>, ranging from 91 to 96%. Among the various compositions, 10%ZnO-TiO₂ composite showed better catalytic activity, recyclability, and reusability, showing no significant loss in activity after up to four cycles, compared to the 3%ZnO-TiO₂. This increased performance is ascribed to the superior number of acidic sites provided by the greater ZnO content in the 10%ZnO-TiO₂ composite. The chief gains of the current method are minimalism, quick reaction time, excellent yields, economical catalyst, and the ability to recover and reuse the catalyst. ADME analysis of these compounds was accomplished to recognize the promising candidates. Similarly, the binding mechanism of the synthesized molecules was examined in molecular docking studies with the targeted enzymes, DNA Gyrase B (PDB ID: 1EI1) and CYP51 (PDB ID: 1EA1). The synthesized title products, diethyl (2,4-difluorobenzylamino)(substituted phenyl)methylphosphonate and diethyl hydroxy(substituted phenyl)methylphosphonate, were tested for antimicrobial activity, and the screening results revealed that α-aminophosphonates displayed more promising antimicrobial activity compared to α-hydroxyphosphonate derivatives, whereas two α-aminophosphonate derivatives, with 3-nitrophenyl and 2,4-dichlorophenyl substituents, showed excellent activity, close to standards.</p> Graphical abstract <p></p>