Global food security is increasingly challenged by growing populations and environmental constraints, with wheat serving as one of the key crops essential for human nutrition. However, wheat yields are continuously threatened by a variety of biotic and abiotic stressors, creating a persistent gap between achievable and actual production. Addressing this issue requires the deployment of advanced strategies and technologies to develop wheat varieties that are both high-yielding and stress-resilient. The advent of high-throughput omics technologies has revolutionized the characterization of plant-associated microbiomes, facilitating a transition to multi-omics approaches in wheat research. Methodologies, including amplicon sequencing, metagenomics, metatranscriptomics, metaproteomics, metabolomics, and viromics, allow comprehensive exploration of microbial diversity, function, and ecological interactions. The integration of these approaches provides a robust framework to understand how microbial communities influence wheat growth, health, and stress tolerance. This chapter reviews the application of wheat meta-omics in advancing food security, highlighting beneficial and pathogenic microbial interactions. It also explores how combined meta-omics strategies and artificial intelligence can elucidate complex plant–microbe networks, providing actionable insights for stress mitigation and genomic-oriented wheat improvement.