The world's forests are currently facing the impacts of climate change and associated extreme events, which are adversely affecting natural ecosystems and increasing risks of forest mortality. In the Mediterranean region, where water is already a limiting factor, drought stress is having a severe impact on tree growth. Different species have developed physiological mechanisms to cope with drought, and an increase in water use efficiency has been observed in several drought-tolerant species. This paper analysed the growth trends and the ecophysiological responses of four widespread Mediterranean species (Pinus pinaster Aiton, Pinus pinea L., Pinus halepensis Mill and Quercus ilex L.) to climate variability, in a natural reserve of the Vesuvio National Park (Southern Italy). Dendrochronological analyses were used to measure tree-ring widths and to estimate basal area increments for each species. Stable isotope analyses of δ13C were performed to calculate intrinsic water use efficiency on an annual scale for the four species. Climate-growth relationships suggested that temperatures, in particular annual minimum temperature, had a significant impact on the growth of each species. The species that showed the highest resistance to hot periods and water scarcity was Pinus halepensis, presenting the highest intrinsic water use efficiency values. On the other hand, Quercus ilex was found to be the most susceptible to prolonged drought periods and sensitive to changes in precipitation, resulting in the weakest growth rates during extreme heat and cold periods. Our study demonstrated the importance of better understanding the ecophysiological responses of each species to develop sound conservation and forest management plans.