On the basis of contents discussed in the manuscript, this summary chart illustrates post-parturient metabolic alterations resulting in the decline in reproductive performance in dairy cows. The postpartum dairy cow is over-stressed due to parturition labor, lactation demands, possible exposure to heat stress, reduced dry matter intake (DMI), uterine involution, and initiation of the reproductive cycle. Due to these problems, post-parturient dairy cows usually suffer from a negative energy balance (NEBAL). NEBAL leads to endocrine and metabolic alterations initiated by low insulin, high glucose consumption, decreased insulin growth factor (IGF-1), and high growth hormone (GH) activity, leading to high non-esterified fatty acid (NEFA) response. NEFA is oxidized in the liver for energy support, leading to ketosis, and ultimately results in the development of fatty liver due to the accumulation of triglycerides (TGs). A higher prepartum body condition score (BCS) is determined as a predisposing factor for extensive mobilization of body fat reserves in the form of NEFA. Fat mobilization and protein metabolism lead to the depletion of the most required fatty acids and amino acids for reproduction and body well-being. These changes are the primary cause of secondary metabolic diseases such as hypocalcemia, ruminal acidosis, and displaced abomasum. Furthermore, they ultimately cause changes in the biochemical profile of the ovarian follicles, contained oocyte, developing embryo, corpus luteum (CL), and uterus, which ultimately result in low conception rates (CRs), whereas they also trigger endocrine changes at the pituitary–hypothalamus-ovary axis, including changes in estrogen (E2), gonadotrophins (GnRH), luteinizing hormone (LH), and progesterone (P4). Additionally, these aforementioned changes also influence the immune system of postpartum dairy cows through activation of LPS, cytokines, and Toll-like receptors (TLRs). These phenomena predispose the cows to infections and inflammatory conditions and thus contribute to the decline in CRs.