Weather data from the Prosecco area were used to apply a proposed model for estimating δ18O values in wine (HV; Hermann and Voerkelius 2008) and to determine the spatio-temporal variability of these values. Eleven reference stations provided meteorological data from 1973 to 2017. The model revealed interannual and spatial variability similar to that observed for other grape varieties or viticultural areas, and we highlight the need for more careful consideration of meteorological factors in causing variation in δ18O values. Meteorological modeling of isotopic values can help constrain sampling procedures aimed at collecting representative data from different Prosecco production areas and estimating δ18O ranges for each year in the “Prosecco” region. Estimated values revealed a significant degree of temporal variability across the 11 sites and, consequently, across years. δ18O values for 36 bottled “Prosecco” wines collected from 2012 to 2017 were compared with the range defined by the HV model for each corresponding year, with good data consistency.