AbstractTheAlternaria alternataapple pathotype adversely affects apple (Malus domesticaBorkh.) cultivation. However, the molecular mechanisms underlying enhanced resistance to this pathogen in apple remain poorly understood. We have previously reported thatMdWRKY75expression is upregulated byA. alternatainfection in ‘Sushuai’ apples. In this study, we discovered that overexpression ofMdWRKY75eincreased the resistance of transgenic apple lines toA. alternatainfection, whereas silencing this gene enhanced susceptibility toA. alternatainfection. Furthermore, we found that MdWRKY75e directly binds to theMdLAC7promoter to regulate the biosynthesis of laccase and increase the biosynthesis of lignin duringA. alternatainfection. Moreover, the thickening of the cell wall enhanced the mechanical defense capabilities of apple. In addition, we found that jasmonic acid remarkably inducedMdWRKY75eexpression, and its levels in transgenic apple lines were elevated. These results indicate thatMdWRKY75econfers resistance to theA. alternataapple pathotype mainly via the jasmonic acid pathway and that pathogenesis-related genes and antioxidant-related enzyme activity are involved in the disease resistance ofMdWRKY75etransgenic plants. In conclusion, our findings provide insights into the importance ofMdWRKY75efor resistance toA. alternatainfection in apples.