As a top predator, the endangered Australian sea lion (Neophoca cinerea) is a sentinel of ecosystem change, where population trends can reflect broader shifts in the marine environment. The population of this endemic pinniped was historically diminished by commercial sealing, and recovery has been slowed by fishery interactions and disease. They are exposed to pollutants, but the impact is unknown. Hookworm (Uncinaria sanguinis) is transmitted through lactation to 100% of neonatal pups and has been identified as a contributor to population decline. Here, a multifactorial approach using novel qPCR and ddPCR, as well as lysozyme and IgG assays, serum protein electrophoresis and flow cytometry was used to examine the relationship of immune phenotypes of developing Australian sea lion pups from two South Australian colonies to hookworm disease status and age. Interleukin 6 peaked early in the patent period of infection and was followed by an increase in acute phase proteins, based on lysozyme and SPE. Additionally, a rise in the B: T lymphocyte ratio was observed followed by serum IgG, which peaked around the time of hookworm elimination. Greater IL6 mRNA and related immune parameters in animals with lower-intensity hookworm infection, as well as a further increase after parasiticide treatment (ivermectin), indicated modulation of the host immune response by hookworm. This study shows the importance of multivariate eco-immunological studies, adds deeper insights to this host-pathogen relationship and provides foundational knowledge for the design of future studies evaluating other potential threats, such as marine pollutants and environmental change.