<p>Sweetpotato black rot, caused by the fungus <i>Ceratocystis fimbriata</i>, adversely affects yield and postharvest quality. We applied integrated transcriptomic and metabolomic profiling to elucidate resistance mechanisms in the black rot–resistant cultivar SS23 versus the susceptible cultivar GS08. Phenotypically, SS23 developed substantially milder symptoms and smaller lesions, whereas GS08 suffered extensive root damage. Multi-omics integration revealed that SS23 mounted a rapid defense response characterized by the upregulation of defense-related genes (e.g., peroxidase, chitinase) and a coordinated metabolic reprogramming that increased levels of resistance-associated compounds, including the amino acids leucine and proline and sesquiterpenoids such as plumericin. By contrast, GS08 exhibited a delayed transcriptional response and suppression of amino acid metabolic pathways. Our analyses highlight the central role of terpenoid biosynthesis in resistance: SS23 activated terpene synthases (<i>IbTPS</i>) together with cytochrome P450s to promote production of antifungal terpenoids, whereas GS08 primarily upregulated the upstream mevalonate pathway enzyme HMG-CoA reductase (<i>IbHMGR</i>) without corresponding downstream specialization. Volatile profiling detected 13 terpenoids in SS23 following infection (including isoterpinolene) versus 6 in GS08. To the best of our knowledge, we are the first to report the identification of specific antifungal terpenoids, such as isoterpinolene, being induced in sweetpotato roots in response to black rot. Tightly interconnected gene–metabolite networks in SS23 appear to constrain pathogen progression, whereas metabolic dysregulation in GS08 strongly correlated with susceptibility. These findings emphasize terpenoid-pathway manipulation as a promising strategy for developing black rot–resistant sweetpotato and nominate several core genes as candidate molecular markers for precision breeding.</p>