The potato tuber moth (PTM), Phthorimaea operculella Zeller (Lepidoptera: Gelechiidae), is one of the most destructive pests of potato crops worldwide. Although it has been reported how potatoes integrate the early responses to various PTM herbivory stimuli by accumulatively adding the components, the broad-scale defense signaling network of potato to single stimuli at multiple time points are unclear. Therefore, we compared three potato transcriptional profiles of undamaged plants, mechanically damaged plants and PTM-feeding plants at 3 h, 48 h, and 96 h, and further analyzed the gene expression patterns of a multitude of insect resistance-related signaling pathways, including phytohormones, reactive oxygen species, secondary metabolites, transcription factors, MAPK cascades, plant–pathogen interactions, protease inhibitors, chitinase, and lectins, etc. in the potato under mechanical damage and PTM infestation. Our results suggested that the potato transcriptome showed significant responses to mechanical damage and potato tuber moth infestation, respectively. The potato transcriptome responses modulated over time and were higher at 96 than at 48 h, so transcriptional changes in later stages of PTM infestation may underlie the potato recovery response. Although the transcriptional profiles of mechanically damaged and PTM-infested plants overlap extensively in multiple signaling pathways, some genes are uniquely induced or repressed. True herbivore feeding induced more and stronger gene expression compared to mechanical damage. In addition, we identified 2976, 1499, and 117 genes that only appeared in M-vs-P comparison groups by comparing the transcriptomes of PTM-damaged and mechanically damaged potatoes at 3 h, 48 h, and 96 h, respectively, and these genes deserve further study in the future. This transcriptomic dataset further enhances the understanding of the interactions between potato and potato tuber moth, enriches the molecular resources in this research area and paves the way for breeding insect-resistant potatoes.