<p><i>Elizabethkingia anophelis</i> is an emerging multidrug-resistant pathogen of significant clinical concern, yet little is known about the evolutionary and translational dynamics of its resistance genes. This study aimed to analyze codon and amino acid usage patterns in the genome of <i>E. anophelis</i> strain 502 and three resistance genes (<i>blaB-11</i>,<i> blaCME-1</i>, and <i>blaGOB-6</i>) to understand the forces shaping their evolution and expression. The genome exhibited moderate codon usage bias, while resistance genes displayed distinct patterns, reflecting gene-specific selection pressures. Nucleotide composition favoured adenine and thymine at synonymous positions, and relative synonymous codon usage revealed strong preference for specific codons, with exclusive usage of the UAA stop codon in resistance genes. Neutrality analysis indicated minimal mutational influence, suggesting that natural selection predominantly shapes codon choice, and translational selection indices indicated moderate optimization of highly expressed genes. Amino acid composition analysis highlighted hydrophilic profiles with moderate aromaticity, and correlation analysis linked codon bias with GC content, translational selection, and protein properties. These findings provide insights into the evolutionary constraints and translational optimization of antibiotic resistance genes in <i>E. anophelis</i>, offering a framework for understanding their adaptation and persistence under antimicrobial pressure and establish the first codon usage landscape of this organism as a reference for future studies.</p>