In this study, two (2) new methoxy-chalcone derivatives [(E)-1-(2,4-dimethoxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (5a) and (E)-3-(4-methoxyphenyl)-1-(2,4,5-trimethoxyphenyl)prop-2-en-1-one (5b)] were designed and synthesized by condensation reaction of 2,4-dimethoxy acetophenone as well as 2,4,5-trimethoxy acetophenone with 4-methoxybenzaldehyde using NaOH as the catalyst. The products were crystallized with ethanol and dried to constant weight. The percentage yield was calculated. The purity of the samples wereconfirmed using TLC and melting point were determined. The structure of the products were verified on the foundation of FT-IR, proton (1H-NMR). Molecular docking studies were carried out using Auto dock vina of pyrex to predict its antimicrobial potentials, and the docked compound was visualized using discovery studio visualizer. The receptor (Bacteria DNA gyrase) was obtained from protein data bank (PDB) with I.D of (4DUH). Compound 5a had binding energy of (-7.6kcal/mol) while compound 5b had (-7.0kcal/mol). The two compound exhibited good molecular interaction with receptor, which include the hydrogen bonding and hydrophobic interactions. The result from this work shows that both compounds had good binding affinity to the receptor, and are predicted to inhibit the bacteria DNA gyrase. Compound 5a had showed to have superior activity when compared to compound 5b. The compounds haveexhibited great potentials to serve as a lead for the development of novel antimicrobial agents.