Migraine is a recurrent headache disorder characterized by episodes of acute pain. The overall objective of this work, was to test the hypothesis that the NLRP3 inflammasome is involved in the pathophysiology of migraine and that NLRP3 blockade may represent a novel strategy for migraine management through the design of novel inhibitors. The phenotype of NLRP3 knockout (NLRP3 KO) mice has been investigated in a mouse model of migraine induced by the i.p. administration of nitroglycerin (NTG). Using the same model, were tested the effects of MCC950, a standard NLRP3 inhibitor able to cross the blood-brain barrier, and of 7n, a new NLRP3 inhibitor that does not cross the blood-brain barrier. Migraine-like signs were evaluated as periorbital mechanical allodynia (PMA) with von Frey filaments. NLRP3 KO female mice did not develop PMA after a single or repeated NTG administrations. Different results were obtained with male NLRP3 KO mice, which were sensitive to the effects of NTG. Similarly, the administration of MCC950 was able to treat and prevent NTG-induced PMA only in female mice but not in male mice. The 7n inhibitor was unable to prevent NTG-induced PMA. This work demonstrates that the modulation of NLRP3 may be a valuable strategy to prevent or block the onset of migraine. In addition, this study highlights two main features: 1) a particularly relevant sex dimorphism; 2) the NLRP3 involved in migraine onset is located in the central nervous system and the ability to cross the blood-brain barrier is mandatory to produce anti-migraine effects.