The transition period of dairy cattle is characterized by a number of metabolic, endocrine, physiologic, and immune adaptations, including the occurrence of negative energy balance, hypocalcemia, liver dysfunction, overt systemic inflammatory response, and oxidative stress status. The degree and length of time during which these systems remain out of balance could render cows more susceptible to disease, poor reproductive outcomes, and less efficient for milk production and quality. Studies on both monogastrics and ruminants have reported the health benefits of nutraceuticals (e.g. probiotics, prebiotics, dietary lipids, functional peptides, phytoextracts) beyond nutritional value, interacting at different levels of the animal's physiology. From a physiological standpoint, it seems unrealistic to disregard any systemic inflammatory processes. However, an alternate approach is to modulate the inflammatory process per se and to resolve the systemic response as quickly as possible. To this aim, a growing body of literature underscores the efficacy of nutraceuticals (active compounds) during the critical phase of the transition period. Supplementation of essential fatty acids throughout a 2-month period (i.e. a month before and a month after calving) successfully attenuates the inflammatory status with a quicker resolution of phenomenon. In this context, the inflammatory and immune response scenario has been recognized to be targeted by the beneficial effect of methyl donors, such as methionine and choline, directly and indirectly modulating such response with the increase of antioxidants GSH and taurine. Indirectly by the establishment of a healthy gastrointestinal tract, yeast and yeast-based products showed to modulate the immune response, mitigating negative effects associated with parturition stress and consequent disorders. The use of phytoproducts has garnered high interest because of their wide range of actions on multiple tissue targets encompassing a series of antimicrobial, antiviral, antioxidant, immune-stimulating, rumen fermentation, and microbial modulation effects. In this review, we provide perspectives on investigations of regulating the immune responses and metabolism using several nutraceuticals in the periparturient cow.