Although oncolytic viruses provide attractive vehicles for cancer treatment, their adverse effects are largely ignored. In this work, rat C6 glioblastoma cells were subcutaneously xenografted into mice, and a thymidine kinase-deficient oncolytic vaccinia virus (oncoVV) induced severe toxicity in this model. However, oncoVV-HddSBL, in which a gene encoding Haliotis discus discus sialic acid-binding lectin (HddSBL) was inserted into oncoVV, significantly prolonged the survival of mice as compared to the control virus. HddSBL reduced the tumor secreted serum rat IL-2 level upregulated by oncoVV, promoted viral replication, as well as inhibited the expression of antiviral factors in C6 glioblastoma cell line. Furthermore, HddSBL downregulated the expression levels of histone H3 and H4, and upregulated histone H3R8 and H4R3 asymmetric dimethylation, confirming the effect of HddSBL on chromatin structure suggested by the transcriptome data. Our results might provide insights into the utilization of HddSBL in counteracting the adverse effects of oncolytic vaccinia virus.