Sickle cell disease (SCD) is a prevalent hemoglobinopathy that leads to various complications, including hepatobiliary diseases, which are often underrecognized. Cholelithiasis and choledocholithiasis, resulting from accelerated pigment gallstone formation due to increased hemolysis, are common in SCD patients. This case series aims to raise awareness of the heightened risk of biliary disease in SCD and emphasize the need for early screening and management strategies. We present four cases of adult SCD patients who developed gallstones, each requiring medical intervention for biliary complications. The first case involved a 47-year-old woman with SCD and choledocholithiasis, presenting with right upper quadrant pain and jaundice. She underwent a laparoscopic cholecystectomy and endoscopic retrograde cholangiopancreatography (ERCP) for stone removal. The second case described a 25-year-old woman with a history of SCD, who had hyperbilirubinemia and dilated common hepatic duct. She successfully underwent ERCP and laparoscopic cholecystectomy after cholelithiasis was confirmed. The third case involved a 34-year-old man with acute abdominal pain and right-sided testicular pain, diagnosed with gallstones and early cholecystitis. Despite plans for surgery, he signed out against medical advice. The fourth case was a 28-year-old woman with recurrent acute chest syndrome, who presented with abdominal pain and was found to have multiple gallstones. She underwent laparoscopic cholecystectomy, but developed acute chest syndrome postoperatively, requiring exchange transfusion. All patients experienced post-surgical recovery, although one patient had complications related to acute chest syndrome. Hepatobiliary manifestations in SCD include cholelithiasis, choledocholithiasis, and other liver-related issues. The formation of pigmented gallstones is a direct result of chronic hemolysis, where increased bilirubin levels contribute to stone formation. The incidence of cholelithiasis in SCD patients is significant, with factors such as hemoglobin levels and bilirubin elevation increasing the likelihood of gallstone formation. Symptomatic gallstones often present with right upper quadrant pain, which can be exacerbated by vaso-occlusive crises. Early intervention, including elective cholecystectomy, can help prevent complications like choledocholithiasis, biliary colic, and cholecystitis. Despite a lack of formal guidelines for routine cholecystectomy in asymptomatic patients, evidence supports early surgical management to prevent further complications and reduce the need for emergent procedures. This case series highlights the importance of early screening and elective cholecystectomy for SCD patients at risk of biliary disease. Early intervention can prevent acute complications, reduce hospitalizations, and improve the quality of life for patients with SCD. Future research and guidelines should focus on establishing protocols for screening and management of gallstone-related hepatobiliary complications in this population.