Objective To investigate the effects of ginseng polysaccharides (GSP) on ethanol-induced behavioral sensitization and its possible mechanism. Methods Eighty Kunming mice were randomly divided into five groups: blank, model, GSP low-dose (100 mg / kg), GSP middle-dose (200 mg / kg), and GSP high-dose (400 mg / kg). Except for the blank group, all animals were provided water or ethanol freely. The concentration of ethanol was gradually increased from 3% to 12% by increasing ethanol 3% every four days. After a 4-day conversion period, the initial dose of 3% ethanol was provided to establish a behavioral sensitization model. Ethanol consumption and locomotor activities of each group were measured daily during the experimental period. During the transition period, an open field test (OFT) was carried out. Activation of behavioral sensitization was determined by locomotor test during the expression period. Western blot and real- time PCR were used to detect protein and mRNA expression, respectively, of ERK, p-ERK, and c-fos, in the prefrontal cortex. Results Three doses of GSP significantly reduced the hyperactivity caused by 9% and 12% ethanol during the transition period, and significantly inhibited the increase of locomotor activity and ethanol intake induced by 3% alcohol challenge (day 25). In addition, middle and high doses of GSP could significantly modulate the number of crawls and standing times in the OFT. GSP could significantly inhibit ethanol-induced increases in malondialdehyde levels in the prefrontal cortex, as well as increased superoxide dismutase and catalase activities. Western blot and real-time PCR result showed that GSP could downregulate protein and mRNA overexpression of p-ERK and c-fos in the prefrontal cortex. Conclusions GSP had an inhibitory effect on ethanol-induced behavioral sensitization and ethanol intake in mice, and this effect may be related to the ERK/ c-fos pathway.