Sweet potato virus disease (SPVD) is the most devastating viral disease in sweet potato (Ipomoea batatas (L.) Lam.), causing substantial yield losses worldwide. We conducted a systemic investigation on the spread, transmission, and pathogenesis of SPVD. Field experiments conducted over two years on ten sweet potato varieties showed that SPVD symptoms first occurred in newly developed top leaves, and spread from adjacent to distant plants in the field. The SPVD incidence was mainly (but not only) determined by the resistance of the varieties planted, and each variety exhibited a characteristic subset of SPVD symptoms. SPVD was not robustly transmitted through friction inoculation, but friction of the main stem might contribute to a higher SPVD incidence rate compared to friction of the leaf and branch tissues. Furthermore, our results suggested that SPVD might be latent in the storage root. Therefore, using virus-free storage roots and cuttings, purposeful monitoring for SPVD according to variety-specific symptoms, and swiftly removing infected plants (especially during the later growth stages) would help control and prevent SPVD during sweet potato production. Comparative transcriptome analysis revealed that numerous genes involved in photosynthesis, starch and sucrose metabolism, flavonoid biosynthesis, and carotenoid biosynthesis were downregulated following SPVD, whereas those involved in monolignol biosynthesis, zeatin biosynthesis, trehalose metabolism, and linoleic acid metabolism were upregulated. Notably, critical genes involved in pathogenesis and plant defense were significantly induced or suppressed following SPVD. These data provide insights into the molecular changes of sweet potato in response to SPVD and elucidate potential SPVD pathogenesis and defense mechanisms in sweet potato. Our study provides important information that can be used to tailor sustainable SPVD control strategies and guide the molecular breeding of SPVD-resistant sweet potato varieties.