Acute soft skull syndrome is an uncommon complication of patients with sickle cell anemia. Here, we report a case of an adult patient in Sudan with the acute soft syndrome, with our aim of providing more knowledge on this type of complication. The 20-year old patient, with a known history of sickle cell anemia, presented with a 1-day history of headache and joint pain. The complaint continued after admission, with increasing headache severity and development of rapid skull swelling, which indicated the rare sickle cell disease complication known as an acute soft head syndrome. Conservative management resulted in good response and rapid recovery of this case of acute soft skull syndrome with sickle cell anemia mainly related to skull infraction.