Evidence suggests that factors associated with a family history of neurodegenerative disease (fhNDD) may influence outcomes following a concussion. However, the relevance of these findings in adolescent populations has not been fully explored. Therefore, the present study sought to evaluate the relationship between fhNDD and neurological outcomes following an adolescent concussion. Data from a local pediatric concussion clinic were used to compare adolescents with (n = 22) and without (n = 44) an fhNDD. Clinical symptom burden, emotional health, cardio-autonomic function, and cognitive performance were assessed at initial (~2 weeks) and follow-up (~5 weeks) post-injury evaluations. Cardio-autonomic function was assessed at rest and during isometric handgrip contraction (IHGC). Results indicated no significant group differences in emotional health or cognitive performance. Across evaluations, those with an fhNDD exhibited greater somatic symptom severity, alterations in HRV at rest, and early blunted cardio-autonomic reactivity during IHGC compared to those without an fhNDD. These findings suggest that positive fhNDD is negatively associated with clinical symptomology and cardio-autonomic functioning following an adolescent concussion. Further, these findings encourage clinicians to utilize a comprehensive neurological evaluation to monitor concussion recovery. Future studies should look into exploring the role of specific neurodegenerative processes and conditions on concussion outcomes in adolescents.