ABSTRACTPlants are no longer considered standalone entities; instead, they harbor a diverse community of plant growth-promoting rhizobacteria (PGPR) that aid them in nutrient acquisition and can also deliver resilience. Host plants recognize PGPR in a strain-specific manner; therefore, introducing untargeted PGPR might produce unsatisfactory crop yields. Consequently, to develop a microbe-assistedHypericum perforatumL. cultivation technique, 31 rhizobacteria were isolated from the plant’s high-altitude Indian western Himalayan natural habitat andin vitrocharacterized for multiple plant growth-promoting attributes. Among 31 rhizobacterial isolates, 26 produced 0.59 to 85.29 μg mL−1indole-3-acetic acid and solubilized 15.77 to 71.43 μg mL−1inorganic phosphate; 21 produced 63.12 to 99.92% siderophore units, and 15 exhibited 103.60 to 1,296.42 nmol α-ketobutyrate mg−1protein h−11-aminocyclopropane-1-carboxylate deaminase (ACCD) activity. Based on superior plant growth-promoting attributes, eight statistically significant multifarious PGPR were further evaluated for anin plantaplant growth-promotion assay under poly greenhouse conditions. Plants treated withKosakonia cowaniiHypNH10 andRahnella variigenaHypNH18 showed, by significant amounts, the highest photosynthetic pigments and performance, eventually leading to the highest biomass accumulation. Comparative genome analysis and comprehensive genome mining unraveled their unique genetic features, such as adaptation to the host plant’s immune system and specialized metabolites. Moreover, the strains harbor several functional genes regulating direct and indirect plant growth-promotion mechanisms through nutrient acquisition, phytohormone production, and stress alleviation. In essence, the current study endorsed strains HypNH10 and HypNH18 as cogent candidates for microbe-assistedH. perforatumcultivation by highlighting their exclusive genomic signatures, which suggest their unison, compatibility, and multifaceted beneficial interactions with their host and support the excellent plant growth-promotion performance observed in the greenhouse trial.IMPORTANCEHypericum perforatumL. (St. John’s wort) herbal preparations are among the top-selling products to treat depression worldwide. A significant portion of the overallHypericumsupply is sourced through wild collection, prompting a rapid decline in their natural stands. Crop cultivation seems lucrative, although cultivable land and its existing rhizomicrobiome are well suited for traditional crops, and its sudden introduction can create soil microbiome dysbiosis. Also, the conventional plant domestication procedures with increased reliance on agrochemicals can reduce the diversity of the associated rhizomicrobiome and plants’ ability to interact with plant growth-promoting microorganisms, leading to unsatisfactory crop production alongside harmful environmental effects. CultivatingH. perforatumwith crop-associated beneficial rhizobacteria can reconcile such concerns. Based on a combinatorialin vitro,in vivoplant growth-promotion assay andin silicoprediction of plant growth-promoting traits, here we recommend twoH. perforatum-associated PGPR,Kosakonia cowaniiHypNH10 andRahnella variigenaHypNH18, to extrapolate as functional bioinoculants forH. perforatumsustainable cultivation.