Purpose <p>We investigated the association between physical activity and the risk of aortic dissection in the UK Biobank.</p> Methods <p>The analytical dataset included 452,994 participants aged mainly between 40 and 69 years, recruited from 2006 to 2010. Cox proportional hazards models were used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between physical activity and the risk of aortic dissection.</p> Results <p>During 12.3 years follow-up, 331 aortic dissection cases were identified. No clear association was observed between the highest vs. lowest quintile of frequency of leisure-time physical activity (HR, 95% CIs: 0.84, 95% CI: 0.59–1.19; <i>P</i>_trend&#xa0;=&#xa0;0.88), moderate physical activity (1.11, 0.71–1.72, <i>P</i>_trend&#xa0;=&#xa0;0.51), or vigorous physical activity (1.06, 0.76–1.48, <i>P</i>_trend&#xa0;=&#xa0;0.74) and risk of aortic dissection. A suggestive inverse U-shaped association was observed for moderate vs. low levels of walking and aortic dissection risk with HRs (95% CIs) of 1.00 (reference), 0.80 (0.53–1.20), 0.63 (0.41–0.97), 0.63 (0.39–1.02) and 0.78 (0.55–1.11) for walking 2, 4, 5, 6, and 7 times/week, respectively. This association was slightly strengthened after exclusion of participants with prevalent CVD, cancer and respiratory disease at baseline. In analyses using MET-hours/week as the metric, a suggestive inverse association was observed for vigorous physical activity (0.66, 0.43–0.99; <i>P</i>_trend&#xa0;=&#xa0;0.09), but not for other physical activity domains.</p> Conclusion <p>Overall, we found little evidence of a clear association between physical activity and aortic dissection in the current study. Potential U-shaped inverse associations between frequency of walking and the risk of aortic dissection, and between MET-hours/week of vigorous physical activity and aortic dissection need further study in additional large cohort studies.</p>