The metritis complex (MC), characterizing post-partum uterine diseases in dairy cattle has negative implications on animal welfare, production efficiency, and the economic stability of the dairy industry. The studies in this thesis aimed to investigate the genetic architecture of the metritis complex and identify genomic regions and metabolites associated with the development of MC. Thereby enhancing our understanding of the biological pathways and molecular mechanisms involved in the pathophysiology of MC during the transition period in Jersey and Holstein dairy cattle. Chapter 2 sheds light on the previous work done on MC. The goals of this review were to (1) provide an updated epidemiological profile of uterine ailments, (2) integrate results from genomics, transcriptomics, metabolomics, and proteomics (OMICs) studies to reveal insights on the identified biological pathways modulated during the transitional period and the onset of metritis, and (3) discuss the commonly detected molecular mechanisms in OMICs studies. Chapter 3 utilized genomic profiles to identify genetic variants, genes, and biological pathways that modulate MC development. A genome-wide association study (GWAS) was performed using a single locus mixed linear model on 1,967 Holstein and Jersey cow genotypes (624,460 SNPs), and MC records from three dairy herds. Following this, in-silico functional and gene network analyses were performed to detect biological mechanisms and pathways linked to the development of endometritis, metritis, and pyometra, diseases defined under the metritis complex development. Potential genes were significantly (P ≤ 0.0001) associated with MC and located on chromosomes 12, 10, and 21. These genes are involved in potential metabolic pathways which are directly associated with the mode of transmission for well-known pathogens in the metritis complex. Chapter 4 followed the GWAS with a high-throughput liquid chromatography-mass spectrometry (LC-MS) metabolomic study. The goals of this study were to 1) to identify metabolites associated with the development of MC in multi-parous Jersey and Holstein cows, 2) to detect the molecular pathways linked to the identified metabolites for MC, and 3) and to identify potential metabolomic biomarkers for early detection of uterine disease development in dairy cattle following parturition. A case-control design was employed on transitioning dairy cattle (n=28), at three time points (week 1, 2, and 3 post-calving). The study identified 48 significant (at false discovery rate adjusted P≤0.05) metabolic deviations for MC during the second week post-partum using single point t-test model. Using repeated measurement, 50 metabolites were identified as significant across all three time points. The results from the studies done revealed mechanisms contributing to the development of uterine disease in Jersey and Holstein breeds. These results should be validated and may be used as genomic selection or management tool to decrease the incidence of metritis complex in dairy cattle.