Complex diseases are the result of molecular perturbations in cellular, tissue, and organ systems, and elucidating the complex molecular perturbations within and between cells, tissues, and organs is a main task of modern biomedicine. Recent advances in genomic technologies are enabling multi-tissue, mutli-cellular, and multiomics investigations of disease mechanisms and necessitating systems genomics tools and methodologies that facilitate multidimensional data integration as well as applications of such approaches to dissect complex diseases. My dissertation research encompasses both method development and application studies of traumatic brain injury (TBI). On the method front, to effectively integrate multi-omics data to better explain the etiology of complex diseases, I developed the Mergeomics web server to implement a computational pipeline that integrates multiomics disease association data with functional genomics and molecular networks to retrieve biological pathways, gene networks, and central regulators critical for disease. To bridge tissue-level omics data with single cell information, I developed MethylResolver for robust deconvolution of bulk tissue DNA methylation profiles into known and unknown cellular contents. From the application end, I conducted multi-tissue temporal transcriptomic studies of TBI at single cell resolution, revealing target cells, pathways, and cell-cell networks at different stages of TBI that are amendable to therapeutics. In summary, the open-access methodologies I developed facilitate systems genomics studies of complex diseases, and the spatiotemporal investigations of TBI at single cell resolution offered novel mechanistic insights into disease pathophysiology and uncovered new therapeutic avenues.