Background: Neurodegenerative diseases (NDs) are one of the main causes of disability and dependence that have a great impact both on the quality of life of people with disabilities and their families. A majority of people with NDs receive care and support from the family, but there is no tool in Spain with which to measure whole-family QOL. The aim of this study was the translation, cultural adaptation, and validation of the FQOLS-Dementia into Spanish to assess FQOL among family members of individuals with NDs who live in the Spain-Portugal cross-border area. Method: The Spanish version was translated and adapted following the international guidelines for cross-cultural adaptation tests. A sample of 300 family caregivers was interviewed, applying an adapted version of the Family Quality Survey (FQOLS-Dementia). Confirmatory factor analysis was performed to validate the factor structure, and convergent validity was examined with Pearson's correlation coefficients of the global FQOL with the domains. Internal consistency reliability was determined using Cronbach's alpha. Results: The domain structure of the FQOLS-ND showed a good fit. In the convergent validity, it was found that the total score and the subscale domain scores were associated with the global FQOL score, except for the Values domain. Internal consistency of nine domain subscales was strong (α = 0.80 to 0.91), and excellent for the total FQOL (α = 0.85) and the global FQOL (α = 0.87). Conclusion: The FQOLS-ND presented good validity and reliability in caregiver families with individuals with ND, so its application shows its usefulness in detecting areas of improvement and intervention strategies for FQOL in the Spain-Portugal cross-border area.