This study has addresses the question whether speleothems from DeSoto Caverns (Childersburg, AL) can be used as paleoclimate archives for the Southeast USA. The monitoring program encompassed determination of cave air CO2, cave ambient conditions (i.e., air temperature, humidity), drip-water geochemistry and local rainfall amount, and stable isotopes of oxygen and hydrogen (Tuscaloosa, AL). The substantial attenuation of drip water isotope ranges (-3.1 to – 5.3 ‰ V-SMOW) relative to rainwater (-1.2 to -6.4 ‰ V- SMOW) is likely caused by mixing of freshwater with residual evaporated water in the epikarst zone. The cave drip water δ18O shows an interannual negative trend from the warm/dry year (2012) to the relatively cool/wet year (2013) suggesting that evapotranspiration above the cave plays an important role in drip water δ18O variability. Drip water Ca, Mg and Sr and Mg/Ca and Sr/Ca ratios exhibit lower values and higher ratios, respectively, during the warm/dry relative to the cool/wet year. The interannual rainfall amount variability likely exerts a dominant control on the elemental concentrations and elemental ratios of the drips. Cave air pCO2 varies seasonally with high values (up to 5.0 atm ×103) during summer when cave air flow is in stagnation mode and low values (down to 0.48 atm ×103) during winter when cave air flow is in ventilation mode. The data suggest that seasonal variations in the concentration of cave air CO2 affect the δ13C of drip water and by extension that of speleothem δ13C values. The documented abrupt hydroclimate changes at ~5 ka in a DeSoto stalagmite is synchronous with the reduction of the North Atlantic Deep Water (NADW) production suggesting the latter being the likely controlling factor. The periodic (68 ± 4 yrs periodicity) switches of seasonal rainfall amount dominance from winter to summer and back are a prominent feature of the mid-to-late Holocene δ18O time series of the speleothem. The observed 68 ± 4 yrs periodicity in stalagmite 18O agrees well with the ~ 70 yrs periodicity of the Atlantic Multidecadal Oscillation (AMO) suggesting the latter played a dominant role in the hydroclimate changes in the southeastern US during the late Holocene.