Rabies is an almost always fatal disease caused by rabies virus (RABV). Once RABV enters the central nervous system, the mortality rate is almost 100%. Therefore, preventing RABV from entering the nervous system is crucial for the development of anti-RABV therapeutics. Here, we found that the L-type calcium channel Cav1.2 pore-forming subunit (Cav1.2) and potassium calcium-activated channel subfamily M alpha 1 (KCa1.1) are involved in the internalization of RABV using an siRNA approach. RABV glycoprotein interacts with Cav1.2, a process that is required for the subsequent activation of the channel. The activated Cav1.2 then interacts with and activates KCa1.1 to regulate the endocytosis of RABV by promoting the F-actin polymerization. Importantly, diltiazem, a blocker of Cav1.2 and an FDA-approved drug, has been shown to substantially reduce mortality in mice infected with RABV. Approximately 70% of mice survived following treatment with diltiazem at 50 mg/kg, whereas the 25 mg/kg dose resulted in 26% survival. Our findings suggest that Cav1.2 is a promising target for the development of antiviral drugs against rabies and enhances our comprehension of the RABV entry mechanism.