The Mediterranean basin is indicated as a hot spot of climate change, which is an area whose climate is especially responsive to variations. The insular environment is one of the most threatened by the current climate change, especially in terms of drought events, with serious consequences for water scarcity and water stress. This issue is even enhanced in small islands, whose ecosystems are among more sensitive to climatic changes and water availability. The stable isotope composition of hydrogen (δ2H) and oxygen (δ18O) in precipitation is globally recognized as a powerful natural tracer in the water cycle and represents the starting point to investigate hydrological processes. The understanding of the prevailing factors that drive the isotopic variability of precipitation in the Mediterranean is therefore essential to unravel the hydrological processes and to ensure proper and sustainable management of potentially vulnerable resources to climate change. Here, we discuss the results of multi-year isotopic monitoring in the period 2014–2021 of monthly precipitation collected on Pianosa Island (Italy), a small island located in the northern Tyrrhenian (western Mediterranean). The lower slope and intercept of the Local Meteoric Water Line of the island compared to the Global Meteoric Water Line indicated warmer and drier climatic conditions, suggesting the existence of sub-cloud evaporation processes of raindrops during precipitation, especially in summer. The mean δ18O of precipitation was lower with respect to other sites placed at higher elevation in this Mediterranean region, due to the lack of summer precipitation which were generally enriched in heavy isotopes. Temperature and amount effects may explain part of the δ18O variability observed at the monthly and seasonal scale. An HYSPLIT-based moisture uptake analysis indicated the area between the western Mediterranean basin, Italy, and the Adriatic Sea as the region that supplied most of the humidity associated with monthly precipitation samples on Pianosa Island. Less moisture was picked from the northwestern areas of Europe, the North Atlantic Ocean, the proximal Atlantic Ocean, the Iberian Peninsula and North Africa. Consistently with the rainout effect, the higher the moisture fraction picked from the more proximal regions, the more positive the δ18O of precipitation occurring on Pianosa Island; conversely, the higher the percentage of moisture sourced from more distal regions, the more negative the δ18O. A multiple linear model was proposed to predict the δ18O of monthly precipitation from temperature, precipitation amount and moisture origin data, which explained 45% of the δ18O variability. The deuterium excess variability on the island was partly controlled by the local climatic variables, whose effect potentially modifies the original d-excess signature imprinted at the moisture source. No relationship was found between the precipitation deuterium excess and moisture sources, suggesting that more attention should be paid when using the deuterium excess as a tracer of moisture origin, especially in the Mediterranean.