At the start of the war with the eastern warlords, Guo Si was sent to assist Niu Fu to improve the defences of Mei County.

After Hu Zhen and Lü Bu suffered a major defeat at the hands of Sun Jian and Dong Zhuo's retreat to Chang'an, Niu Fu, Guo Si and Li Jue were ordered to station themselves in Shan (present-day Shaanxi), which was the battle front against the anti-Dong-Zhuo coalition.

Along with his comrades, Fan Chou, Li Jue and Zhang Ji, Guo Si initially wanted to make Niu Fu their leader, but the latter was so scared and listened to his subordinate, Huchi'er (胡赤兒), to flee with the treasures he had saved.

Guo Si, along the other three generals, then pleaded with the de facto leader of the Han central government, Wang Yun, for an amnesty since they were Dong Zhuo's most trusted aides.

Jia Xu suggested that they should take the opportunity to launch a strike at Chang'an since the Liang Province forces' power base was still intact after the coup.

Wang Yun sent Xu Rong and Hu Zhen to fight the Liang Province forces en route at An'feng, but Xu Rong was killed in the first encounter and Hu Zhen persuaded his troops to join the rebels thus greatly increasing the size of the rebel force.

The four then demanded high ranks, and Guo Si and Li Jue even thought about assassinating the emperor to take the throne, however was dissuaded from doing so by Fan Chou and Zhang Ji.

Taking advantage of the chaos and massive confusion caused by the civil war between Li Jue and Guo Si, Emperor Xian sneaked out of Chang'an and was rescued by the leader of the White Wave Bandits, Yang Feng.

The power of Li Jue and Guo Si had greatly diminished resulting from previous infighting and the loss of Emperor Xian.

Guo Si was eventually slain by his subordinate Wu Xi (伍習), who led his remnants to join Li Jue in 197.