Phytophthora nicotianae is a highly destructive soil-borne plant pathogen that leads to significant economic losses in agriculture. Chitooligosaccharides (COS) are popular biostimulant which can promote plant growth and responses to biotic and abiotic stresses. However, the role of COS in resisting the black-shank disease (BSD, caused by P. nicotianae) through regulating plant root exudates and rhizosphere microecology remains unclear. An integrative analysis, based on the transcriptome analysis, root exudate metabolome, and biochemical tests, revealed the secretion of more sugar-related differential metabolites and differential gene expressions expressed under COS treatment during the disease resistance response. Furthermore, increased accumulation of trehalose and trehalose 6-phosphate as well as increased activity of trehalose 6-phosphate synthase was observed under COS treatment after inoculation with P. nicotianae. Additionally, sucrose and glucose, which positively regulate resistance to plant diseases, also exhibited elevated levels. Beneficial microorganisms, such as Bacillus were enriched in the rhizosphere soil during COS treatment. The isolated Bacillus velezensis T-2 strain exerted inhibitory activity on P. nicotianae, which was enhanced by the presence of trehalose. This multi-omics study of transcriptome, metabolome, and microbiomics revealed that COS enhances resistance to tobacco BSD by regulating sugar homeostasis and recruiting beneficial microorganisms.