Chronic inflammation is one of the most prominent features of Alzheimer's disease (AD). Little is known about how brain hemodynamics and oxygenation are affected by AD-related inflammation. Here, we use two-photon phosphorescence lifetime imaging with an oxygen-sensitive dye “Oxyphor 2P” to measure the partial pressure of oxygen (pO2) before and during endotoxin-induced neuroinflammation in cortical vessels of a mouse model of AD. Capillary red blood cell flux (RBC flux) was measured through two-photon phosphorescence intensity microscopy. To induce chronic inflammation, we injected lipopolysaccharide (LPS) intraperitoneally, daily for two weeks, in female APPswe: PS1dE9 mice and age-matched wild-type (WT) controls. Intravascular pO2 and RBC flux were measured in the somatosensory cortex before the LPS injection, on week 1 (day 7), and week 2 (day 15) during the LPS injection. Our results demonstrate that LPS-induced systemic inflammation leads to significant decreases in cortical intravascular pO2 while showing a negligible effect on capillary RBC flux. Moreover, AD mice are more susceptible to inflammation with more pronounced cortical pO2 reduction in comparison to WT mice. Our findings suggest that inflammation plays a key role in AD-related disruptions of cerebral tissue metabolism of oxygen.