He hailed form Zhuojun 涿郡 (moderm Hebei河北) and was a fellow student of the great commentator Zheng Xuan 鄭玄 under the instruction of Ma Rong 馬融, a scholar that tried reconciling the two schools of the new-text and the old-text tradition of the Confucian Classics. Lu Zhi favoured an essential study of a whole text corpus over the traditional method to comment each sentence and paragraph.
Under Emperor Ling 漢靈帝 (r. 167-189) he was appointed erudite (boshi 博士) at the National University (taixue 太學), yet in 175 he became governor (taishou 太守) of the commandery of Jiujiang 九江, later of Lujiang 盧江, a position in which he suppressed the uprising of the native population.
Later on he was made court gentleman for consultation (yilang 議郎) and was allowed to instruct courtiers of the Dongguan Archives 東觀 in the Five Classics. He also took part in the compilation of the official dynastic history Hanji 漢紀. He later rose to the office of palace attendant (shizhong 侍中) and Imperial Secretary (shangshu 尚書).
When the rebellion of the Yellow Turbans 黃巾 broke out in 184 CE he took over the command of the Northern army 北中郎將 that suppressed the rebel army under Zhang Jiao 張角. Yet the rebel defeated him, so that Lu Zhi was put into jail. Shortly after the Emperor pardoned him and reappointed him as his chief secretary.
Lu Zhi opposed the powerful general-in-chief (da jiangjun 大將軍) He Jin 何進, who wanted to invite general Dong Zhuo 董卓 to lead his troops into the capital to extinguish the eunuch clique. When Dong Zhuo occupied the capital in 189 and planned overthrowing Emperor Ling, Lu Zhi was the only minister opposing the mighty warlord. Dong Zhuo wanted to kill him, but the Confucian scholar Cai Yong 蔡邕 rescued him, so that he was able to retire safely.
Lu Zhi's classical commentaries Shangshu zhangju 尚書章句 and Sanli jiegu 三禮解詁 are lost.