Type 2 diabetes (T2D) has become an increasingly challenging health burden due to its high morbidity, mortality, and heightened prevalence worldwide. Although dietary and nutritional imbalances have long been recognized as key risk factors for T2D, the underlying mechanisms remain unclear. The advent of nutritional systems biology, a field that aims to elucidate the interactions between dietary nutrients and endogenous molecular entities in disease-related tissues, offers unique opportunities to unravel the complex mechanisms underlying the health-modifying capacities of nutritional molecules. The recent revolutionary advances in omics technologies have particularly empowered this incipient field. In this review, we discuss the applications of multi-omics approaches toward a systems-level understanding of how dietary patterns and particular nutrients modulate the risk of T2D. We focus on nutritional studies utilizing transcriptomics, epigenomomics, proteomics, metabolomics, and microbiomics, and integration of diverse omics technologies. We also summarize the potential molecular mechanisms through which nutritional imbalances contribute to T2D pathogenesis based on these studies. Finally, we discuss the remaining challenges of nutritional systems biology and how the field can be optimized to further our understanding of T2D and guide disease management via nutritional interventions.