Hypercalcemia of malignancy confers a poor prognosis. This systematic review evaluated published cases of hypercalcemia of malignancy presenting with acute pancreatitis (AP), in terms of clinical presentation and outcomes. A comprehensive review of PubMed and Embase until March 18, 2020, was conducted. Studies were included if they reported on patients with hypercalcemia of malignancy and AP with attempts to exclude other etiologies of hypercalcemia and AP. Two independent reviewers selected and appraised studies using the Murad tool. Thirty-seven cases were identified. Mean (standard deviation) age was 44.8 (2.46) years. Mean (standard deviation) presenting corrected calcium was 14.5 (0.46) mg/dL. Parathyroid carcinoma (21.6%) and multiple myeloma (21.6%) were the most common malignancies. Cases were classified as severe (37.8%), mild (21.6%), and moderately severe (18.9%), whereas 21.6% did not report severity. Necrotizing pancreatitis developed in 21.6% of cases. Most cases were treated with intravenous hydration and bisphosphonates or calcitonin/calcitonin analogues. Mortality was 32.4% during the same presentation of AP. Among mortality cases, 10 of 12 had severe AP, and 5 of 12 had necrotizing pancreatitis. Degree of hypercalcemia did not influence mortality. Acute pancreatitis associated with hypercalcemia of malignancy is rare. One in 3 patients with this presentation may not survive AP.