Simple Summary The transition period is largely marked by a decline in dry matter intake (DMI) that often leads to a negative energy balance (NEB) which, along with exaggerated insulin resistance (IR), increasing the mobilization of body fat reserves, leads to higher blood non-esterified fatty acid (NEFA) and/or beta-hydroxybutyric acid (BHBA) concentrations. These confounding factors adversely affect animal health and lactation performance. This study evaluated the impact of pre- and post-partum berberine (BBR) supplementation as a novel approach to the regulation of nutritional metabolism in transition dairy goats. In summary, BBR supplementation (2 and 4 g/d) elevated the DMI and energy balance (EB) in pre- and post-partum goats, as well as enhancing liver activity indices, showing the potential of the new therapeutic strategy in the prevention of metabolic dysfunction in transition dairy goats and in attaining an improved lactation performance as well as health. The objectives of this study were to evaluate the alleviating effects of the isoquinoline alkaloid berberine (BBR) on the energy balance (EB), glucose and insulin metabolism, and liver functionality in transition dairy goats, as reflected by blood metabolites and enzymes. Twenty-four primiparous Saanen goats were randomly allocated to four groups. Goats in each group received, ad libitum, the same basal diet during the pre- and post-partum periods of evaluation. Goats received daily0, 1, 2, or 4 g BBR (coded as CON, BBR1, BBR2, and BBR4, respectively). Dry matter intake (DMI) and milk yield were recorded daily. Blood samples were collected on days -21, -14, -7, 0, 7, 14, and 21 relative to kidding, and individual body condition scores (BCSs) were also recorded. Supplementation with either BBR2 or BBR4 increased (p < 0.05) pre- and post-partum DMI, increasing (p < 0.05) the intakes of net energy for lactating and metabolizable proteins. BBR2 and BBR4 increased (p < 0.05) post-partum milk production as well as fat-corrected milk (FCM), energy-corrected milk (ECM), and feed efficiency, indicating the alleviating effect of BBR on the negative energy balance (NEB) in transition goats. The daily ingestion of either 2 or 4 g BBR reduced (p < 0.05) plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) and increased (p < 0.05) the dynamic change in the liver activity index (LAI) and liver functionality index (LFI), implying its hepatoprotective effect on transition goats. Overall, the results suggest that BBR supplementation of at least 2 g/d may help to ameliorate insulin resistance (IR) and fat metabolism disorders initiated by the NEB in transition dairy goats.