Zoledronate (ZDA) is a bisphosphonate used to treat hypercalcemia that commonly occurs with malignancy, multiple myeloma, and bone metastases from solid tumors. It acts primarily by decreasing osteoclastic activity, thereby slowing the release of skeletal calcium. However, a potential adverse effect of ZDA is hypocalcemia that can be symptomatic, especially in patients with risk factors such as hypomagnesemia, hypoparathyroidism, renal failure, and vitamin D deficiency. We report the case of a patient with extensive stage small cell lung cancer with multiple osseous and visceral metastases who developed symptomatic hypocalcemia following ZDA administration. Significant clinical improvement occurred following administration of calcium and vitamin D, and his calcium levels returned to normal within a few days. Due to the high incidence of vitamin D deficiency and the low accuracy of clinical risk factors to predict vitamin D deficiency, screening for vitamin D deficiency before administration of ZDA may be appropriate.