Diet and physical activity (PA) have been studied extensively in epidemiology as single or combined lifestyle factors; however, their interaction has not been studied thoroughly. Studying potential synergisms between lifestyle components with a comprehensive interaction analysis, including additive measures of interaction, provides key insights into the nature of their joint effect and helps target interventions more effectively. First, a comprehensive review was conducted to assess the potential research gap regarding reported interaction analyses conducted in studies assessing the Mediterranean diet (MedDiet) in combination with PA on all-cause mortality. Thereafter, we prospectively assessed the joint association of the MedDiet with PA on all-cause mortality in the Seguimiento Universidad de Navarra (SUN) cohort, followed by both multiplicative and additive interaction analyses. The conjoint effect of low adherence to the MedDiet and low PA observed an increased risk greater than the individual risk factors, suggesting a potential additive interaction or synergism between both exposures, with relative risk due to interaction (RERI) and (95 % confidence interval (95 % CI)) = 0.46 (-0.83 to 1.75) and attributable proportion (95 % CI) due to interaction of 36 % (-0.62, 1.34). No multiplicative interaction was detected. Studying interactions between lifestyle factors, such as the MedDiet and PA, is particularly relevant given the current research gaps in studying the complexities of combined aspects of lifestyle in comparison with isolated behaviours. Our findings underline the important public health message of adhering to both the MedDiet and PA for the prevention of premature mortality.