Sport-related concussions in youth and adolescent athletes most commonly resolve within one week without residual symptoms, with athletes resuming full participation following return to play guidelines. A small percentage of athletes have persistent symptoms that cause significant morbidity, some of whom are ultimately diagnosed with post-concussion syndrome. In these athletes, symptoms in the emotional domain can be more prolonged than other domains, with athletes reporting anxiety and depression months to years following injury. A prior personal or family history of pre-existing mood disorder or attention-deficit/hyperactivity disorder increases the risk of a prolonged duration of symptoms. In this case series, we discuss two cases of post-concussion syndrome in adolescent athletes with a past personal or family history of attention-deficit/hyperactivity disorder, anxiety, and depression treated by a combination of cognitive behavioral therapy and medication with ongoing persistent symptoms. There is increased need for mental health screening in all athletes to identify individuals at risk for post-concussion syndrome. Early identification of at-risk individuals allows the interdisciplinary care team to discuss expectations for the athlete and family regarding duration of symptoms.