Advances in medical therapy have changed sickle cell disease (SCD), a life-threatening haemoglobinopathy, into a chronic illness of childhood extending into adulthood. Restrictions in daily life activities, behavioural inhibitions and associated social stigma have led to a significant psycho-socio-economic burden on patients and their families. This study was conducted to estimate the prevalence and severity of psychological comorbidities, namely stress, anxiety and depression among SCD patients and to assess the effect of psychosocial intervention through counselling, patient education and familial and social support. A total of 374 SCD patients aged >12 years, visiting the outpatient department (OPD), were recruited for the study and were assessed for psychological comorbidities using the validated Hindi version of the Depression Anxiety Stress Scale-42 (DASS-42). The questionnaires were administered by a trained psychologist. Out of these, 98 patients who consented for further participation were assessed for the effect of intervention in the form of verbal guidance sessions, self-help group sessions and provision of printed educational material. We observed that 53.74% of 374 patients were affected with at least one of the psychological comorbidities. Stress, anxiety and depression affected 27.54%, 49.20% and 32.89% of patients, respectively. The majority of affected patients had symptoms in the moderate to extremely severe range. We observed that the depression score increased by a factor of 0.419 and 0.558 for anxiety and stress, respectively. Interestingly, we observed a significantly higher prevalence of depression in females (chi(2) (1) = 8.808, p = .0030). We also observed that prevalence and severity scores for stress, anxiety and depression among the patients showed a significant reduction in response to the psychosocial intervention. Our findings show a higher prevalence of psychological comorbidities in SCD patients and highlight the need for early identification and remediation of psychological comorbidities in SCD patients.