Groundwater inflow to a subtropical seepage lake was estimated using a transient isotope-balance approach for a decade (2001–2011) with wet and dry climatic extremes. Lake water δ18O ranged from +0.80 to +3.48 ‰, reflecting the 4 m range in stage. The transient δ18O analysis discerned large differences in semiannual groundwater inflow, and the overall patterns of low and high groundwater inflow were consistent with an independent water budget. Despite simplifying assumptions that the isotopic composition of precipitation (δP), groundwater inflow, and atmospheric moisture (δA) were constant, groundwater inflow was within the water-budget error for 12 of the 19 semiannual calculation periods. The magnitude of inflow was over or under predicted during periods of climatic extreme. During periods of high net precipitation from tropical cyclones and El Niño conditions, δP values were considerably more depleted in 18O than assumed. During an extreme dry period, δA values were likely more enriched in 18O than assumed due to the influence of local lake evaporate. Isotope balance results were most sensitive to uncertainties in relative humidity, evaporation, and δ18O of lake water, which can limit precise quantification of groundwater inflow. Nonetheless, the consistency between isotope-balance and water-budget results indicates that this is a viable approach for lakes in similar settings, allowing the magnitude of groundwater inflow to be estimated over less-than-annual time periods. Because lake-water δ18O is a good indicator of climatic conditions, these data could be useful in ground-truthing paleoclimatic reconstructions using isotopic data from lake cores in similar settings.