Apple leaf spot, caused by the Alternaria alternata apple pathotype (AAAP), is an important fungal disease of apple. To understand the molecular basis of resistance and pathogenesis in apple leaf spot, the transcriptomes of two apple cultivars ‘Hanfu’ (HF) (resistant) and ‘Golden Delicious’(GD) (susceptible) were analyzed at 0, 6, 18, 24 and 48 h after AAAP inoculation by RNA-Seq. At each time point, a large number of significantly differentially expressed genes (DEGs) were screened between AAAP-inoculated and uninoculated apple leaves. Analysis of the common DEGs at four time points revealed significant differences in the resistance of ‘HF’ and ‘GD’ apple to AAAP infection. RLP, RNL, and JA signal-related genes were upregulated in both cultivars to restrict AAAP development. However, genes encoding CNLs, TNLs, WRKYs, and AP2s were only activated in ‘HF’ as part of the resistance response, of which, some play major roles in the regulation of ET and SA signal transduction. Further analysis showed that many DEGs with opposite expression trends in the two hosts may play important regulatory roles in response to AAAP infection. Transient expression of one such gene MdERF110 in ‘GD’ apple leaves improved AAAP resistance. Collectively, this study highlights the reasons for differential resistance to AAAP infection between ‘HF’ and ‘GD’ apples which can theoretically assist the molecular breeding of disease-resistant apple crops.