Psychosocial and affective comorbidities are common in sickle cell disease (SCD) and can strongly influence disease outcomes, especially those related to pain such as frequency and intensity of pain, use of emergency- and hospital-based care and opioid use. Depression, anxiety, sleep disorders, and substance use challenges are among the common comorbidities that inform the patient experience of SCD. Underlying neurocognitive changes may also contribute to the expression of affective disorders in people with SCD. The neurobiological basis of these comorbidities in SCD is being investigated. In this mini-review, we discuss psychosocial and affective disorders that can coexist in children and adults with SCD and highlight how these common psychological pathologies may interact with complications associated with SCD. Patients with SCD should be screened for these comorbidities using standardized screening tools and managed appropriately to improve outcomes.