The health benefits of the Mediterranean diet (MedDiet) and of physical activity (PA) have been widely documented. However, no longitudinal studies have investigated their combined effect on mortality. We assessed the individual and combined effects of adherence to the MedDiet and PA on all-cause mortality. We used data from 19,467 participants from a prospective cohort of Spanish university graduates, the SUN cohort, followed-up between December 1999 and February 2016. Adherence to the MedDiet was assessed using four different dietary scores, categorizing the quantitative scores into tertiles of adherence. To assess multiple dimensions of PA, an 8-item score was built. Multivariable Cox regression models were used to study the individual and combined relationship of adherence to the MedDiet and PA with all-cause mortality. During a median follow-up of 10.3years, we registered 305 deaths. Compared with the lowest adherence to the MedDiet (<20 in the modified Mediterranean diet score), better adherence (23-30 points) was associated with lower mortality (multivariable-adjusted hazard ratio [HR]=0.66, 95% confidence interval [CI]: 0.46-0.96). Engaging in moderate or high levels of PA (versus lower levels) was associated with 44% and 52% relative reductions in mortality, respectively. High adherence to the MedDiet combined with engaging in higher amounts of PA showed a HR=0.36 (95% CI: 0.19-0.67). We documented that the combined effect of better adherence to the MedDiet and increased PA had multiplicative effects on mortality risk reduction.