The manipulation of cytosolic Ca concentration ([Ca]) plays a crucial role in the study of Ca signaling and the therapy of its affected diseases. Nanotechnology enables the development of nanotransducers for targeted, non-invasive, highly spatiotemporal, and on-demand [Ca] regulation by responding to external energy fields to activate Ca channels, in situ deliver Ca, or release the payload of chemical modulators. As considerable strides have been made in Ca signaling-related fundamental research and applications in recent years, in this article, it is tried to present a thorough review of nanotransducer-based [Ca] manipulation, from the working principle to specific applications. Focusing on the design rationale and constructions of nanotransducers, the interactions between nanotransducers and Ca channels are highlighted, as well as the downstream effectors of Ca signaling pathways, followed by their representative biomedical applications in disease treatment and neuromodulation. Moreover, despite the enormous progress made to date, nanotransducer-regulated Ca signaling still confronts obstacles, and several scientific issues urgently need to be resolved. Thus, to provide brief and valid instructions for the development of nanotransducers for the regulation of Ca signaling, proposals on how to improve the nanotransducer-based [Ca] manipulation as well as future challenges and prospects are discussed.