Glucose enhances memory in a variety of species. In humans, glucose administration enhances episodic memory encoding, although little is known regarding the neural mechanisms underlying these effects. Here we examined whether elevating blood glucose would enhance functional MRI (fMRI) activation and connectivity in brain regions associated with episodic memory encoding and whether these effects would differ depending on the emotional valence of the material. We used a double-blind, within-participants, crossover design in which either glucose (50g) or a saccharin placebo were administered before scanning, on days approximately 1 week apart. We scanned healthy young male participants with fMRI as they viewed emotionally arousing negative pictures and emotionally neutral pictures, intermixed with baseline fixation. Free recall was tested at 5 min after scanning and again after 1 day. Glucose administration increased activation in brain regions associated with successful episodic memory encoding. Glucose also enhanced activation in regions whose activity was correlated with subsequent successful recall, including the hippocampus, prefrontal cortex, and other regions, and these effects differed for negative vs. neutral stimuli. Finally, glucose substantially increased functional connectivity between the hippocampus and amygdala and a network of regions previously implicated in successful episodic memory encoding. These findings fit with evidence from nonhuman animals indicating glucose modulates memory by selectively enhancing neural activity in brain regions engaged during memory tasks. Our results highlight the modulatory effects of glucose and the importance of examining both regional changes in activity and functional connectivity to fully characterize the effects of glucose on brain function and memory.