Plants influence the microbiome and abiotic properties of soils to a substantial extent, which could cause feedback effects on subsequent plantings. Plant-soil feedback (PSF) can be positive, negative, or neutral, contributing to management implications for a variety of agricultural systems. The goal of the dissertation research is to uncover the microbial drivers of negative plant-soil feedback using a model weed species, common ragweed (Ambrosia artemisiifolia L.), that is native to North America and has expanded its geographic range across Europe and Asia. Specifically, we: 1) conducted literature research for novel methodologies and approaches in screening the soil microbiome for weed biocontrol agents and bioherbicide; 2) investigated microbiome-mediated variation in PSF intensity across organic and conventional farming systems using A. artemisiifolia as the model plant; 3) examined the role of root exudates in driving soil microbiome-mediated PSF between organic and conventional farming systems; and 4) explored the feasibility of GHz ultrasonic imaging in screening large-insert metagenomic libraries of weed suppressive rhizospheres for novel natural product discovery of herbicidal compounds. The second chapter greenhouse PSF study showed that microbiome-mediated PSF of common ragweed was mostly negative and differed in intensity between organic and conventional farming systems. The PSF was driven by a small subset of the microbiome. The third chapter growth chamber study suggested that root exudates of common ragweed shifted the soil microbiome and drove the different PSF responses between organic and conventional system microbiomes. The fourth chapter exploratory work with the GHz ultrasonic chip showed a potential alternative for high throughput screening of metagenomic libraries for natural product discovery featuring a bioactive clone uncovered from the rhizosphere of A. artemisiifolia. Overall, our work shows that distinct PSF responses between organic and conventional farming systems can be mediated by the soil microbiome and root exudates. These studies are the first to indicate variability in PSF intensities by farming management systems and in comparison to whole plant versus root exudate contributions. Our research provides further understanding of the mechanisms of negative PSF and contributes to novel insights into weed management strategies in regenerative agriculture.