Mental fatigue is, for many, a very distressing and long-term problem after a traumatic brain injury (TBI) or stroke. This will make it more difficult for the individual to return to work and resume social activities, and it can take several years to find the right balance between rest and activity in daily life, to find strategies and to accept the new situation. The aim of this study was to evaluate the effect of an advanced mindfulness program following a MBSR program, designed for subjects suffering from long-term mental fatigue after a brain injury. The advanced program was based on The Brahma Viharas, meditative practices known for cultivating four mental states: compassion, metta, appreciative joy, and equanimity. Fourteen participants followed the 8-month advanced mindfulness program, with group visits once a month and a final all-day retreat. All the participants were suffering from mental fatigue at least 1 year after a brain injury following a stroke or a TBI. The assessments after the advanced program showed a significant and sustained positive effect on mental fatigue and on tests measuring information processing speed and attention. With mindfulness practice it was possible to improve wakefulness during meditation and, above all, improve the mental fatigue levels. We propose that mindfulness is a promising treatment for mental fatigue after a stroke or TBI.