Rabies, which is caused by the rabies virus (RABV), is an ancient zoonosis that has a high mortality rate. Previous studies have indicated that recombinant RABV expressing canine interleukin-6 (rHEP-CaIL6), induced more virus-neutralizing antibodies than parental RABV in mice following intramuscular immunization. To investigate the immune response induced in the CNS by rHEP-CaIL6 after intranasal or intracranial administration in mice, the permeability of the blood-brain barrier (BBB), the infiltration of CD3 T cells, and innate immune response-related effector molecules in the CNS were examined. It was observed that infection of rHEP-CaIL6 led to enhanced BBB permeability following intranasal infection. More CD3 T cells infiltrated into the central nervous system (CNS) in mice infected with rHEP-CaIL6 than in those infected with the HEP-Flury strain. Furthermore, rHEP-CaIL6 induced an increased expression of innate immune response-related effector molecules, compared with the parental HEP-Flury strain, within the CNS. Taken together, these findings suggest that rHEP-CaIL6 induced stronger immune responses in mice brains, which is more beneficial for virus clearance. These results may also partly illustrate the role of IL6 in RABV infection.