Plants respond to cold temperatures through a divergent Ca-signaling network that includes the proteins CBL and CIPK. The Amur grape  ( Vitis  amurensis) is a cold-tolerant wild grape species native to China. Putative CBL and CIPK genes (designated as VaCBLs and VaCIPKs) were surveyed in V.  amurensis. The transcripts of 8 VaCBLs and 19 VaCIPKs encoded in this genome were confirmed. The VaCBLs showed preferential interaction with distinct VaCIPKs in yeast, among which VaCIPK18 physically interacted with all 8 VaCBLs in yeast and in  planta, indicating that VaCIPK18 could function as a node regulator. These multiple interactions of VaCIPK18 were dependent on the C-terminal regulatory domain (NAF). VaCIPK18 was ubiquitously expressed in various tissues and was highly induced by cold, drought, salt, and ABA. Transient expression of a VaCIPK18‐GFP fusion protein in Arabidopsis mesophyll protoplasts indicated its localization in the nucleus and plasma membrane. The NAF domain of VaCIPK18 was required for functional homodimerization in yeast as well as in planta. Over-expression of VaCIPK18 in an Arabidopsis  cipk3 mutant rescued the cold sensitivity, but enhanced cold tolerance in wild-type  Arabidopsis. Thus, our study demonstrates that VaCIPK18 positively regulates cold signaling at least partly through the direct transcriptional control of cold-regulated CBFs and modulation of ROS homeostasis. Moreover, VaCIPK18 was found to interact with VaMYB4a in vivo and in vitro. Our findings provide evidence that VaCIPK18 functions as a key node in the CBL-CIPK network and could interact with VaMYB4a to participate in cold response in grape plants.