Sickle cell disease (SCD) is characterized by hemolysis, inflammation, and pain. Mechanisms of pain manifestation are complex, and there is a major gap in knowledge of how the nervous and immune systems interact to contribute to pain and other comorbidities in SCD. Sterile inflammation in the periphery and central nervous system contributes to vascular and neural activation. Cellular and soluble mediators create an inflammatory and neuroinflammatory microenvironment contributing to neurogenic inflammation and acute and chronic pain. In this review we highlight relevant neuro-immune interactions that contribute to the pathobiology of SCD.