Objective To study the effect of lead exposure time on expressions of autophagy proteins including ATG5, Beclin1 and LC3B in the cerebral cortex by establishing the lead exposure model in adult guinea pigs. Methods Eighteen guinea pigs were randomly divided into 4 groups, with 3 in the control group (without lead exposure) and 5 in each of the 3 lead exposure groups with exposure to lead for 15, 60 and 90 days. The model was established using 0.2% lead acetate drinking water, and the control group was given the same amount of normal saline. The expression levels of ATG5, Beclin1 and LC3B proteins were detected by immunohistochemistry. Results Compared with the control group, the positive expressions of ATG5, Beclin1 and LC3B were significantly increased in the 15-day, 60-day and 90-day lead exposure groups (P < 0.05). The expression level of ATG5 in the 90-day lead exposure group was significantly higher than those of other lead exposure groups (P < 0.05). No significant difference was observed in the expression level of ATG5 between the 15-day and 60-day lead exposure groups (P > 0.05).And there was no significant difference in the expression level of Beclin1 or LC3B among the lead exposure groups (P > 0.05). Conclusions Lead drinking water can cause autophagy in the cerebral cortex through the autophagy proteins ATG5, Beclin1 and LC3B. It is speculated that the early autophagic response induced by lead exposure may exert neurotoxic effect on cerebral cortex and cause irreversible damage in adult guinea pigs.