Chronic and acute pain are major comorbidities of sickle cell disease (SCD). Both peripheral and central nervous system mechanisms underlie SCD pain. We investigated the potential roles of endogenous fatty acyl derivatives with endocannabinoid-like activity; using targeted lipidomics of fatty acid ethanolamides and monoacylglycerols, we observed significant reduction of spinal palmitoylethanolamide (PEA) in the humanized, transgenic sickle (HbSS)-BERK mouse model of SCD when compared with healthy HbAA control mice. PEA is a paracannabinoid lipid mediator that acts as a putative mast cell stabilizer and has been evaluated clinically for mechanical, cold, and joint pain, which are all features of SCD pain. Increased p38-MAPK activity in the spinal cord and dorsal root ganglia (DRG) neurons, and cutaneous mast cell activation, contribute to chronic hyperalgesia in sickle cell mice. We provide the first evidence that inhibiting endogenous PEA degradation and administration of exogenous PEA, reduces measures of chronic hyperalgesia via inhibition of peripheral and central mechanisms of pain hypersensitivity in sickle cell mice. PEA alleviated spinal inflammation, oxidative stress, and p38-MAPK activity; in the periphery, inhibited p38-MAPK phosphorylation and nuclear translocation in DRG neurons, reduced mast cell extracellular trap formation, and markers of inflammation in HbSS mice. In addition, PEA treatment prevented and ameliorated acute hyperalgesia incited by hypoxia/reoxygenation challenge in sickle cell mice. Pain may persist even after hydroxyurea and curative therapies in SCD. PEA displayed safety in several clinical studies and has the translational potential to treat pain in SCD without the burden of additional medications.