Background The effects of some atherosclerotic cardiovascular disease ( ASCVD ) risk factors vary according to whether an individual has a family history ( FH x) of premature coronary heart disease ( CHD ). Physical activity ( PA ) is associated with reduced risk of ASCVD , but whether this association varies by FH x status is not well established. Methods and Results We evaluated 9996 participants free of ASCVD at baseline. FH x of premature CHD was defined as CHD occurring in a father before age 55 or mother before age 60. PA , assessed by a Baecke questionnaire, was converted into minutes/week of moderate or vigorous exercise and categorized per American Heart Association guidelines as recommended, intermediate, or poor. Incident ASCVD was defined as incident myocardial infarction, fatal CHD , or stroke. Multivariable‐adjusted Cox hazard models were used. The mean age was 54±6 years, 56% were women, and 21% of black race. Participants with and without a FH x of premature CHD reported similar levels of PA at baseline (423 versus 409 metabolic equivalents of task×min/week, respectively, P =0.852), and ≈40% of both groups met American Heart Association recommended PA levels. Over a mean follow−up of 20.9 years, there were 1723 incident ASCVD events. Compared to those with poor PA adherence to American Heart Association guidelines, participants who reported PA at recommended levels had significantly lower risk of incident ASCVD after adjustment for demographics and lifestyle factors (hazard ratio 0.84, 95% CI 0.74–0.94), but this association was not modified by FH x status ( P −interaction=0.680). Conclusions PA was associated with a reduced risk of ASCVD among individuals with and without a FH x of premature CHD .