Depression is a serious mental illness that includes both behavioral symptoms and cognitive dysfunction. With the growing problem of ineffective treatment, there is a constant need for compounds with rapid antidepressant and procognitive effects. A compound that has shown antidepressant-like activity after single administration in animal models is NLX-101. NLX-101 preferentially activates postsynaptic 5-HT1A heteroreceptors in the prefrontal cortex, stimulating extracellular signal-regulated kinase (ERK1/2) phosphorylation. Thus, this study aimed to evaluate the potential ability of NLX-101 to reverse executive function deficits produced by the administration of the NMDA antagonist MK-801 (0.15 mg/kg i.p.). The potential ability of NLX-101, administered orally, to reverse working memory and cognitive flexibility impairments in male BALB/c mice was tested using the 8-arm radial and two-choice pairwise visual discrimination and reversal tasks. NLX-101 at 4mg/kg increased the percentage of correct responses on days 5 and 6 of the reversal task compared to the MK-801-treated control group. In addition, NLX-101 at 8mg/kg decreased the perseveration index on day 4 and at 4mg/kg on day 5 compared to the MK-801 control group. Interestingly, in the 8-arm radial maze, NLX-101 at doses of 4 and 8 mg/kg reduced the number of errors and the time to complete the 8-arm radial task in MK-801-treated mice Our study showed that activation of cortical 5-HT1A receptors and subsequent stimulation of ERK1/2 reversed working memory and cognitive flexibility deficits induced by NMDA receptor blockade. These results provide a basis for a broader investigation of the role of 5-HT1A receptor-related pathways in cognitive processes.