Background and Aim: Foot-and-mouth disease (FMD) is a highly contagious viral disease that poses significant economic threats to livestock globally. This study aimed to confirm the presence of FMD virus (FMDV) in Egyptian cattle and identify the predominant serotypes contributing to outbreaks in Sharkia and Dakahlia provinces in 2022. Materials and Methods: A total of 65 cattle showing acute FMD symptoms were sampled. Desquamated epithelial tissues and oral secretions were analyzed using reverse transcriptase polymerase chain reaction with universal and serotype-specific primers. Seven representative samples underwent sequencing for phylogenetic and genetic variability analysis. Results: All sampled animals tested positive for FMDV. Serotype A accounted for 72.3% of cases, while 27.7% were serotype O. Sequence analysis identified FMDV serotype A (African topotype, genotype IV) and serotype O (East Africa-3 topotype) as the outbreak-causing strains. The identified strains exhibited significant genetic divergence from the vaccine strains used in Egypt, with notable amino acid substitutions in the VP1 protein’s G-H loop. These mutations raise concerns about the efficacy of existing vaccines against current field strains. Conclusion: The study highlights the ongoing threat of FMD in Egypt, particularly among smallholder cattle farmers. The genetic divergence between circulating FMDV and vaccine strains underscores the need to continuously monitor and update vaccine formulations to enhance disease control efforts. Implementing stricter animal movement regulations and tailored vaccination strategies is essential for effective management.