This study addressed the potential of reduced prebloom irrigation, referred to as primed acclimation (PA), to increase agricultural water-use efficiency (WUE) using a soil-moisture-based irrigation scheduling system in cotton (Gossypium hirsutum L.). To address this, a study was conducted near Camilla, GA, under a variable-rate, center-pivot irrigation system using a Watermark-based automated soil moisture sensing approach to measure soil water potential (SWP) and impose varying irrigation scheduling treatments during the prebloom stage of development. Early season thresholds were −20 (Treatment 1), −40 (Treatment 2), −70 (Treatment 3), to −100 kPa (Treatment 4) prior to flowering. Reductions in prebloom irrigation of up to 17% were noted in this study for the driest thresholds (−100 kPa) with no reduction in lint yield relative to the −20 and −40 kPa thresholds. In some cases, prebloom irrigation was eliminated completely in the drier prebloom threshold treatments with no appreciable yield reductions. In rainfed treatments, episodic drought during flowering (2014) limited plant growth and node production, hastened cutout, decreased boll numbers per plant, produced a more compact boll distribution on the plant, and decreased yield and WUE relative to irrigated treatments. In contrast, season-long rainfed treatments exhibited the highest WUE in 2015 (a wet season). The results of this study conclude that prebloom irrigation thresholds between −70 and −100 kPa appear to be viable for use in a sensor-based PA irrigation scheduling system, whereas episodic drought coinciding with flowering represents a major threat to yield stability and WUE for cotton production in the southeastern United States.