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We compare hydrogen isotopic measurements of long-chain leaf-wax n-alkanes (2Hw; C27, C29, and C31) from Martin Lake, IN, United States of America (USA), with a calcite-based reconstruction of the oxygen isotopic composition of precipitation (18Op) from the same lake. We observe stable and high 2Hw during the Common Era (last 2000 years), which we interpret as growing-season precipitation originating mainly from the Gulf of Mexico and Atlantic. During the Little Ice Age (LIA; 1200-1850 CE), 2Hw values increased by 3-8 ‰, concomitant with a significant decrease in 18Op values by up to 12.5 ‰. Multiple proxy records for this time indicate persistent growing-season drought. We interpret these relatively high 2Hw values, as compared to the 18Op values, as a signal of low relative humidity that resulted in an 2H enrichment in plant source water resulting in high 2H values through enhanced plant water and/or soil evaporation. These results support the occurrence of low humidity conditions during the LIA in the midcontinental USA that also contributed to the marked decline of regional pre-Columbian Mississippian populations.