Ketamine, an NMDA antagonist, is widely used in clinical settings, particularly for its promising role as a rapid antidepressant. Recently, low-dose ketamine has gained attention due to its potential therapeutic benefits. However, the effects of low-dose ketamine on brain function, particularly higher cognitive functions of primate brains, are not fully understood. In this study, we used two macaque monkeys as subjects and found that acute low-dose ketamine administration significantly impairs the ability for arbitrary visuomotor mapping, a form of associative learning essential for flexible behaviors, including executions of learned stimuli-response contingency or learning of new contingencies. We conducted in-depth analyses and identified intrinsic characteristics of these ketamine-induced functional deficits, including lowered accuracy, prolonged time for planning and movement execution, increased tendency to make errors when visual cues are changed from trial to trial, and stronger impact on the associative learning and another key higher cognitive function, working memory. Our results shed new light on how associative learning relies on the NMDA-mediated synaptic transmission of the brain and contribute to a better understanding of the potential acute side effects of low-dose ketamine on cognition, which can help facilitate its safe usage in medical practice.Significance StatementThis study found that acute low-dose ketamine significantly impairs the ability of arbitrary visual motor mapping, a critical form of associative learning for flexible behavior, including stimulus-response contingency learning or learning of new contingencies. We conducted a thorough analysis and identified intrinsic features of ketamine-induced functional deficits, including decreased accuracy, prolonged planning and motor execution time, increased error tendency when visual cues changed from trial to trial, and stronger impact on associative learning and another key higher-order cognitive function, working memory. These findings contribute to a better understanding of the potential acute cognitive side effects of low-dose ketamine and promote its safe use in medical practice.