Daily levels of physical activity vary greatly across individuals and are strongly influenced by genetic background. While moderate levels of physical activity are associated with improved physical and mental health, extremely high levels of physical activity are associated with behavioral disorders such as attention deficit hyperactivity disorder (ADHD). However, the genetic and neurobiological mechanisms relating hyperactivity to ADHD or other behavioral disorders remain unclear. Therefore, we conducted a selective breeding experiment for increased home cage activity starting with a highly genetically variable population of house mice and evaluated the line for correlated responses in other relevant phenotypes. Here we report results through Generation 10. Relative to the Control line, the High-Active line traveled approximately 4 times as far in the home cage (on days 5 and 6 of a 6-day test), displayed reduced body mass at maturity, reduced reproductive success, increased wheel running and open field behavior, decreased performance on the rotarod, decreased performance on the Morris water maze that was not rescued by acute administration of d-amphetamine, reduced hyperactivity from chronically administered low clinical doses of d-amphetamine, and increased numbers of new cells and neuronal activation of the dentate gyrus. Standardized phenotypic differences between the lines were compared to estimates expected from genetic drift to evaluate whether the line differences could have resulted from random effects as opposed to correlated responses to selection. Results indicated line differences in body mass and locomotor responses to low doses of amphetamine were more likely due to selection than drift. The efficacy of low doses of d-amphetamine in ameliorating hyperactivity support the High-Active line as a useful model for exploring the etiology of hyperactivity-associated comorbid behavioral disorders.