It is proposed that mediodorsal thalamus contributes to cognition via interactions with prefrontal cortex. However, there is relatively little evidence detailing the interactions between mediodorsal thalamus and prefrontal cortex linked to cognition in primates. This study investigated these interactions during learning, memory, and decision-making tasks in rhesus monkeys using a disconnection lesion approach. Preoperatively, monkeys learned object-in-place scene discriminations embedded within colorful visual backgrounds. Unilateral neurotoxic lesions to magnocellular mediodorsal thalamus (MDmc) impaired the ability to learn new object-in-place scene discriminations. In contrast, unilateral ablations to ventrolateral and orbital prefrontal cortex (PFv+o) left learning intact. A second unilateral MDmc or PFv+o lesion in the contralateral hemisphere to the first operation, causing functional MDmc–PFv+o disconnection across hemispheres, further impaired learning object-in-place scene discriminations, although object discrimination learning remained intact. Adaptive decision-making after reward satiety devaluation was also reduced. These data highlight the functional importance of interactions between MDmc and PFv+o during learning object-in-place scene discriminations and adaptive decision-making but not object discrimination learning. Moreover, learning deficits observed after unilateral removal of MDmc but not PFv+o provide direct behavioral evidence of the MDmc role influencing more widespread regions of the frontal lobes in cognition.