The pyruvate dehydrogenase kinase (PDK)/pyruvate dehydrogenase (PDH) axis plays a pivotal role in regulating cellular energy metabolism, controlling the flux between the tricarboxylic acid cycle and oxidative phosphorylation. Traditionally viewed through a metabolic lens, this axis is now emerging as a crucial regulator of immune cell function, placing it at the intersection of metabolism and immunity and underscoring its central role in immunometabolism. In this review, we highlight the multifaceted roles of the PDK/PDH axis in orchestrating metabolic reprogramming and immune cell plasticity, highlighting its broader significance across several pathological conditions. Thus, we emphasise the role of this axis in cardiometabolic disease, where its regulation has been shown to highly impact immune and vascular cell functions and to modulate disease progression. Given the promising results from clinical studies beyond the cardiovascular field and from preclinical models of cardiovascular disease, we discuss insights from metabolic reprogramming that may guide therapeutic strategies targeting the immunometabolic dysfunction driving vascular inflammation and its deleterious consequences.