Banana Fusarium oxysporum f. sp. cubense tropical race 4 (Foc-TR4) is a highly destructive pathogen that infects nearly all major banana cultivars and has a tendency to spread further. Secreted proteins play a crucial role in the process of Fusarium wilt infection in bananas. In this study, we analyzed the codon usage bias (CUB) of the Foc-TR4 classical secretory protein genome for the first time and observed a strong bias toward codons ending with C. We found that 572 out of the 14,543 amino acid sequences in the Foc-TR4 genome exhibited characteristics of classical secretory proteins. The CUB was largely influenced by selection optimization pressure, as indicated by the ENC value and neutral plot analysis. Among the identified codons, such as UCC and CCC, 11 were found to be optimal for Foc-TR4 gene expression. Codons with higher GC content and a C base in the third position showed greater selectivity. The CUB in the secretory proteins encoded by Foc-TR4 provides insights into their evolutionary patterns, contributing to the development and screening of novel and effective antifungal drugs.