Sleep, as an active and cyclic behavior, serves diverse functions, such as growth, renovation, and learning/memory consolidation and restoration. In today's hectic life, disorderly lifestyle, psychological and emotional disturbances as well as aging have led to Sleep Deprivation (SD) and its neurological consequences (Mishra et al., 2016[18]). Previous studies have shown that SD could result in such problems as mood alterations, mental injuries, troubled performance, and cognitive disturbances (Motomura et al., 2013[19]; Carskadon, 2011[3]). Quite a few animal studies have also focused on the effects of SD on different brain regions. However, the link between SD and prefrontal cortex has not been thoroughly investigated. The medial Prefrontal Cortex (mPFC) is one of the areas that receive important innervations from the brain stem and hippocampus. This area also plays a fundamental role in memory and learning. The mPFC of rats is generally subdivided into three cytoarchitectonic parts, including Infralimbic Cortex (ILC), Prelimbic Cortex (PLC), and Anterior Cingulate Cortex (ACC) (Pezze et al., 2016[22]). There is scientific evidence that the mPFC is responsible for efficient operation of a number of cognitive functions, such as attention, memory, and behavioral flexibility. The mPFC also mediates cognitive behavior (Granon and Poucet, 2000[8]), which is vulnerable to the disruption caused by SD. Other PFC-mediated cognitive tasks such as memory, planning, decision-making are affected by SD (Wu et al., 2006[30]). Therefore, the present research was designed to fulfill several goals. The main aim of this study was to evaluate the effects of chronic SD on the mPFC structure using stereological methods. The second goal is to find a protective factor to be consumed in case of SD. Curcumin (CUR) is the major curcuminoid of turmeric, which belongs to a member of the ginger family. CUR is known to have a variety of neuroprotective properties (Weber et al., 2005[28]). CUR has been evaluated in a number of neurological diseases, such as Parkinson's disease (Zbarsky et al., 2005[31]), cerebral injury (Ghoneim et al., 2002[7]) and age-associated neurodegeneration (Calabrese et al., 2003[2]). Considering the availability of turmeric and its neuroprotective prosperities, CUR was considered as the agent to be evaluated after SD. This research was conducted on a rat model of SD to find answers to the following questions: