The potential of 77 rhizobacterial isolates to elicit induced systemic resilience (ISResilience) against combined biotic (Fusarium pseudograminearum crown rot) and abiotic (drought) stress in Sorghum bicolor was investigated. ISResilience was determined by assessing disease incidence and severity, plant height and biomass (root and shoots) in rhizobacteria-primed and untreated (naïve) plants inoculated with F. pseudograminearum and subjected to drought stress. Three rhizobacterial isolates (Paenibacillus alvei NAS-6G6, Pseudomonas taiwanensis N66 and Bacillus velezensis N54) showed significant protection of S. bicolor seedlings against biotic, abiotic and combined biotic and abiotic stress. Isolate N54, identified in this study as B. velezensis by 16S rRNA sequencing, was considered as the best performing rhizobacterial isolate to elicit ISResilience. Untargeted ultra-high performance liquid chromatography-high definition mass spectrometry (UHPLC-HDMS) based metabolomics was used to investigate the mechanism by which ISResilience was elicited in S. bicolor by strain N54 (B. velezensis). Comparisons were made with isolates that were previously selected for induced systemic tolerance (ISTolerance) against drought stress (strain N66, Ps. taiwanensis) and induced systemic resistance (ISResistance) against F. pseudograminearum crown rot (strain NAS-6G6, Pa. alvei). The stress alleviation that resulted from treatment with the respective rhizobacterial isolates, was visually confirmed by the use of infrared (IR) thermography. For the metabolomics study, intracellular metabolites were methanol-extracted from rhizobacteria-primed and untreated (naïve) S. bicolor shoots. Extracts were analyzed on an UHPLC-HDMS platform, and the data were chemometrically analyzed to determine metabolite bio-markers related to ISResistance, ISTolerance and ISResilience. The results demonstrated significant treatment-related differences, reflecting differential metabolic reprogramming in S. bicolor in response to the biotic, abiotic and combined stresses. Synergistic effects involved in the lowered susceptibility to crown rot of rhizobacteria-primed S. bicolor seedlings, compared to those left naïve (untreated control) under drought stress conditions and the upregulation of the signatory molecules myo-inositol and riboflavin, provided evidence for the role of crosstalk in the ISResilience observed.