This comprehensive article critically analyzes the advanced biotechnological strategies to mitigate plant drought stress. It encompasses an in-depth exploration of the latest developments in plant genomics, proteomics, and metabolomics, shedding light on the complex molecular mechanisms that plants employ to combat drought stress. The study also emphasizes the significant advancements in genetic engineering techniques, particularly CRISPR-Cas9 genome editing, which have revolutionized the creation of drought-resistant crop varieties. Furthermore, the article explores microbial biotechnology’s pivotal role, such as plant growth-promoting rhizobacteria (PGPR) and mycorrhizae, in enhancing plant resilience against drought conditions. The integration of these cutting-edge biotechnological interventions with traditional breeding methods is presented as a holistic approach for fortifying crops against drought stress. This integration addresses immediate agricultural needs and contributes significantly to sustainable agriculture, ensuring food security in the face of escalating climate change challenges.