There is now a convincing body of evidence from observational studies that the majority of modifiable Alzheimer’s disease and related dementia (ADRD) risk factors are vascular in nature. In addition, the co-existence of cerebrovascular disease with AD is more common than AD alone, and conditions resulting in brain ischemia likely promote detrimental effects of AD pathology. Oxylipins are a class of bioactive lipid mediators derived from the oxidation of long-chain polyunsaturated fatty acids (PUFAs) which act as modulators of both vascular tone and inflammation. In vascular cognitive impairment (VCI), there is emerging evidence that oxylipins may have both protective and detrimental effects on brain structure, cognitive performance, and disease progression. In this review, we focus on oxylipin relationships with vascular and inflammatory risk factors in human studies and animal models pertinent to ADRD. In addition, we discuss future research directions with the potential to impact the trajectory of ADRD risk and disease progression.