Despite the associated adverse outcomes, pharmacologic intervention for covert hepatic encephalopathy (CHE) is not the standard of care. We hypothesized that a video game-based rehabilitation program would improve white matter integrity and brain connectivity in the visuospatial network on brain magnetic resonance imaging (MRI), resulting in improved cognitive function in CHE subjects on measures consistent with the cognitive skill set emphasized by the two video games (e.g., IQ Boost-visual working memory, and Aim and Fire Challenge-psychomotor speed), but also generalize to thinking skills beyond the focus of the cognitive training (Hopkins verbal learning test (HVLT)-verbal learning/memory) and improve their health-related quality of life (HRQOL). The trial included three phases over 8 weeks; during the learning phase (cognitive tests administered twice over 2 weeks without intervening intervention), training phase (daily video game training for 4 weeks), and post-training phase (testing 2 weeks after the video game training ended). Thirty CHE patients completed all visits with significant daily achievement on the video games. In a subset of 13 subjects that underwent brain MRI, there was a significant decrease in fractional anisotropy, and increased radial diffusivity (suggesting axonal sprouting or increased cross-fiber formation) involving similar brain regions (i.e., corpus callosum, internal capsule, and sections of the corticospinal tract) and improvement in the visuospatial resting-state connectivity corresponding to the video game training domains. No significant corresponding improvement in HRQOL or HVLT performance was noted, but cognitive performance did transiently improve on cognitive tests similar to the video games during training. Although multimodal brain imaging changes suggest reductions in tract edema and improved neural network connectivity, this trial of video game brain training did not improve the HRQOL or produce lasting improvement in cognitive function in patients with CHE.