The present study is aimed to elucidate the structural features of novel 3,4-dihydropyrimidin-2(1H)-one urea derivatives required for antibacterial and antifungal activity and to obtain predictive models to guide the rational synthesis of novel activity. A set of twenty-three compounds which had been previously shown to be active against antibacterial and antifungal activity were used in the study. These compounds were optimized using Density functional theory (DFT) for the calculations of molecular descriptors that related the bioactivity of these compounds to their structures. The results signify that the molecular descriptors HOMO,LUMO, η, μ,ω, H, LogP, Area, Volume, PSA, Pol, HBA, S, NOR, used for QSAR model represented the bioactivity of the 3,4-dihydropyrimidin-2(1H)-one urea derivatives. Therefore, the result of the QSAR models shows that the calculated molecular descriptors using quantum chemical method correlate the electronic properties of the molecules to their bioactivities. The results obtained from Multiple linear regression (MLR) analysis are R2 = 0.978, R2Adj = 0.896, F(15, 4) = 12.02197, P-value (F) = 0.013660. The developed quantitative structure activity relation (QSAR) was validated, and it showed the reliability and acceptability of the model.