Blueberries contain an array of phytochemicals that may decrease both inflammatory and oxidative stress. This study determined if pterostilbene, resveratrol, and two anthocyanins commonly found in blueberries, delphinidin-3-O-glucoside and malvidin-3-O-glucoside, would be efficacious in protecting microglia from inflammatory-induced stress signaling. Microglia that were pretreated with blueberry extract (0.25, 0.5, 1, 2 mg/mL) or its components (1, 10, 20, 30 μM pterostilbene, resveratrol, delphinidin-3-O-glucoside, or malvidin-3-O-glucoside) prior to exposure to lipopolysaccharide (100 ng/mL) demonstrated concentration-dependent reductions in nitric oxide and tumor necrosis factor-alpha release and decreased expression of inducible nitric oxide synthase and cyclooxygenase-2. However, much higher concentrations of the individual components than those found in blueberries were needed to demonstrate the effects. For example, 1 mg/mL blueberry extract significantly reduced LPS-induced nitric oxide release; this concentration of blueberry extract contains 2.6 μM malvidin-3-O-glucoside, but when malvidin-3-O-glucoside was tested individually, 20 μM was necessary to observe a significant reduction in nitric oxide release. Therefore the protective effects of blueberries may not be due to any one component, but rather a synergism of the activity of the compounds tested and/or other blueberry compounds not tested here. These results lend further support that blueberry and its active components are able to combat some of the inflammatory mediators of aging at the cellular level.