Bacteria have evolved a variety of enzymes to eliminate endogenous or host-derived oxidative stress factors. The Dps protein, first identified in Escherichia coli, contains a ferroxidase center and protects bacteria from reactive oxygen species damage. There is a lack of knowledge of the role of Dps-like proteins in bacterial pathogenesis. Actinobacillus pleuropneumoniae causes pleuropneumonia, a respiratory disease of swine. The A. pleuropneumoniae ftpA gene is up-regulated during a shift to anaerobiosis, in biofilms and, as found in this study, also by H2O2. An A. pleuropneumoniae ftpA deletion mutant (△ftpA) had increased H2O2 sensitivity, less intracellular viability in macrophages, and decreased virulence in a mouse infection model. Expression of ftpA in an E. coli dps mutant restored wild-type resistance to H2O2. FtpA possesses a conserved ferritin domain containing a ferroxidase site. Recombinant rFtpA bound and oxidized Fe2+ reversibly. Under aerobic conditions, compared with the wild-type strain, the viability of an △ftpA mutant was reduced after extended culture, transition from anaerobic to aerobic conditions, and upon supplementation with Fenton reaction substrates. Under anaerobic conditions, additional H2O2 resulted in a more severe growth defect of △ftpA than under aerobic conditions. Therefore, by oxidizing and mineralizing Fe2+, FtpA alleviates oxidative damage mediated by intracellular Fenton reactions. Furthermore, by mutational analysis, two residues were confirmed to be critical for Fe2+ binding and oxidization, as well as for A. pleuropneumoniae H2O2 resistance. Taken together, this study demonstrates that A. pleuropneumoniae FtpA is a Dps-like protein, playing critical roles in oxidative stress resistance and virulence. IMPORTANCE As a ferroxidase, Dps of Escherichia coli can protect bacteria from reactive oxygen species damage, but its role in bacterial pathogenesis has received little attention. In this study, FtpA of the swine respiratory pathogen A. pleuropneumoniae was identified as a new Dps-like protein. It facilitated A. pleuropneumoniae resistance to H2O2, survival in macrophages, and infection in vivo. FtpA could bind and oxidize Fe2+ through two important residues in its ferroxidase site and protected the bacteria from oxidative damage mediated by the intracellular Fenton reaction. These findings provide new insights into the role of the FtpA-based antioxidant system in the pathogenesis of A. pleuropneumoniae, and the conserved Fe2+ binding ligands in Dps/FtpA provide novel drug target candidates for disease prevention.