Toll-like receptor (TLR)- and retinoic acid-inducible gene I-like receptor (RLR)-mediated type I interferon (IFN) production is essential for providing protection against coronavirus (CoV) infection; the timing of the IFN response relative to CoV replication determines infection outcomes. Optimal NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation is beneficial for the host but aberrant activation may lead to detrimental CoV infection outcomes. Specific CoV infections can activate inflammatory cell death (PANoptosis), thereby inducing cytokine release. CoV disease tolerance occurs in age-, species-, and sex-dependent manners. More studies are needed to define the innate immune response, specifically during severe acute respiratory syndrome (SARS)-CoV-2 (SARS-CoV-2) infection, and to inform the development of candidate therapeutics.