Diabetes mellitus affects millions of people worldwide and is associated with devastating vascular complications. A number of these complications, such as impaired wound healing and poor coronary collateral circulation, are characterised by impaired ischaemia-driven angiogenesis. There is increasing evidence that high-density lipoproteins (HDL) can rescue diabetes-impaired angiogenesis through a number of mechanisms, including the modulation of endothelial cell metabolic reprogramming. Endothelial cell metabolic reprogramming in response to tissue ischaemia is a driver of angiogenesis and is dysregulated by diabetes. Specifically, diabetes impairs pathways that allow endothelial cells to upregulate glycolysis in response to hypoxia adequately and impairs suppression of mitochondrial respiration. HDL rescues the impairment of the central hypoxia signalling pathway, which regulates these metabolic changes, and this may underpin several of its known pro-angiogenic effects. This review discusses the current understanding of endothelial cell metabolism and how diabetes leads to its dysregulation whilst examining the various positive effects of HDL on endothelial cell function.