Cancer is the modern, most persistent serial killer. Cancer cells intelligently recruit and utilize all the biological functions to support their survival, proliferation, and invasion, which require altering and reprogramming a lot of the normal signals and pathways. Calcium (Ca²⁺) is a fundamental secondary messenger involved in most of the regular cellular functions, not only the survival processes but also, the apoptotic death. Cancer cells exhibit unique expression levels of T-type Ca²⁺ channels (TTCC) that vary according to the tumor type, stage, and the channel isoform. The aberrant expression of the TTCC family (Cav3.1, Cav3.2, and Cav3.3) genes in cancer cells significantly contribute in the remodeled Ca²⁺ signaling that mediates many cancer cell functions including mitochondrial energy production, proliferation, angiogenesis, metastasis, and sensitivity to cell death. Accordingly, the TTCC blockers were proposed for their anti-cancer effect. Mibefradil (MBF) (Posicor^®) is a TTCC blocker initially introduced into the pharmaceutical market in 1997 as an FDA-approved antihypertensive drug but voluntarily withdrawn due to drug-drug interactions. 10 years later, MBF was qualified for drug orphan designation by the FDA for the treatment of pancreatic, ovary, and brain cancers. Herein, we investigate the anti-cancer effect of MBF on different cell lines by determining its IC₅₀ and indicate MBF-induced endoplasmic reticulum Ca²⁺ release as a key for the anticancer effect of MBF. Moreover, we identify the effect of MBF on important cytoplasmic organelles such as mitochondria and lipid droplets (LDs). Further, we demonstrate that MBF reduces the number of the lipid droplets and affects the cellular lipid storage by inducing lipolysis in cancer cells.