Targeted approaches have been widely used to help explain physiological adaptations, but few studies have used non-targeted omics approaches to explore differences between diving marine mammals and terrestrial mammals. A rank comparison of undepleted serum proteins from common bottlenose dolphins (Tursiops truncatus) and pooled normal human serum led to the discovery of 11 proteins that appeared exclusive to dolphin serum. Compared to the comprehensive human plasma proteome, 5 of 11 serum proteins had a differential rank greater than 200. One of these proteins, Vanin-1, was quantified using parallel reaction monitoring in dolphins under human care and free-ranging dolphins. Dolphin serum Vanin-1 ranged between 31-106 μg/ml, which is 20-1000 times higher than concentrations reported for healthy humans. Serum Vanin-1 was also higher in dolphins under human care compared to free-ranging dolphins (64 ± 16 vs. 47 ± 12 μg/ml P < 0.05). Vanin-1 levels positively correlated with liver enzymes AST and ALT, and negatively correlated with white blood cell counts and fibrinogen in free-ranging dolphins. Major differences exist in the circulating blood proteome of the bottlenose dolphin compared to terrestrial mammals and exploration of these differences in bottlenose dolphins and other marine mammals may identify veiled protective strategies to counter physiological stress.