Post-operative thirst is common and may cause intense patient discomfort. The aims of this retrospective study conducted in a high-volume post-anesthesia care unit (PACU) were as follows: (1) to examine the prevalence of moderate-to-severe post-operative thirst—defined as a numerical rating scale (NRS) score of 4 or higher, (2) to identify the main risk factors for moderate-to-severe post-operative thirst, and (3) to maximize the efficacy and safety of thirst management through a quality improvement program. During a 1-month quality improvement program conducted in August 2018, a total of 1211 adult patients admitted to our PACU were examined. Moderate-to-severe thirst was identified in 675 cases (55.8%). The use of glycopyrrolate during anesthesia was associated with moderate-to-severe thirst (71.7% versus 66.4%, respectively, p = 0.047; adjusted odds ratio: 1.46, p = 0.013). Following a safety assessment, ice cubes, room temperature water, or an oral moisturizer were offered to patients. A generalized estimating equation model revealed that ice cubes were the most effective means for thirst management—resulting in an estimated thirst intensity reduction of 0.93 NRS points at each 15-min interval assessment (p < 0.001)—followed by room temperature water (− 0.92/time-point, p < 0.001) and the oral moisturizer (− 0.60/time-point; p < 0.001). Patient satisfaction (rated from 1 [definitely dissatisfied] to 5 [very satisfied]) followed a similar pattern (ice cubes: 4.22 ± 0.58; room temperature water: 4.08 ± 0.55; oral moisturizer: 3.90 ± 0.55, p < 0.001). The use of glycopyrrolate—an anticholinergic agent that reduces salivary secretion—was the main independent risk factor for moderate-to-severe post-operative thirst. Our findings may provide clues towards an optimized management of thirst in the immediate post-operative period.