Traumatic brain injury (TBI) represents an important problem of global health. The damage related to TBI is first due to the direct injury and then to a secondary phase in which neuroinflammation plays a key role. NLRP3 inflammasome is a component of the innate immune response and different diseases, such as neurodegenerative diseases, are characterized by NLRP3 activation. This review aims to describe NLRP3 inflammasome and the consequences related to its activation following TBI. NLRP3, caspase-1, IL-1β, and IL-18 are significantly upregulated after TBI, therefore, the use of nonspecific, but mostly specific NLRP3 inhibitors is useful to ameliorate the damage post-TBI characterized by neuroinflammation. Moreover, NLRP3 and the molecules associated with its activation may be considered as biomarkers and predictive factors for other neurodegenerative diseases consequent to TBI. Complications such as continuous stimuli or viral infections, such as the SARS-CoV-2 infection, may worsen the prognosis of TBI, altering the immune response and increasing the neuroinflammatory processes related to NLRP3, whose activation occurs both in TBI and in SARS-CoV-2 infection. This review points out the role of NLRP3 in TBI and highlights the hypothesis that NLRP3 may be considered as a potential therapeutic target for the management of neuroinflammation in TBI.