A new series of polyurea derivatives and its nanocomposites were synthesised by the solution polycondensation method through the interaction between 4 (2-aminothiazol-4-ylbenzylidene)-4-(tert-butyl) cyclohexanone and diisocyanate compound in pyridine. The PU1-3 structure was confirmed using Fourier transform-infrared (FTIR) spectroscopy and characterised by solubility, viscometry, gel permeation chromatography (GPC), and X-ray diffraction (XRD) analysis. In addition, PU1-3 was evaluated by TGA. Polyurea-TiO2nanocomposites were synthesised using the same technique as that of PU1-3 by adding TiO2 as a nanofiller. The thermal properties of PU2TiO2a-d were evaluated by TGA. Moreover, the morphological properties of a selected sample were examined by SEM and TEM. In addition, PU1-3 and PU2TiO2a-d were examined for antimicrobial activity against certain bacteria and fungi. The PU1-3 showed antibacterial activity against some of the tested bacteria and fungi, as did PU2TiO2a-d, which increased with the increase in TiO2 content. Furthermore, molecular docking studies were displayed against all PU1-3 derivatives against two types of proteins. The results show that the increase in the strength of π-H interactions and H-donors contributed to improved binding of PU2 compared to PU1 andPU3. The docking of 1KZN against the tested polymers suggests an increase in the docking score of PU2, then PU1, and PU3, which is in agreement with the antibacterial study.