He hailed from Shangcai 上蔡 (modern Shangcai, Henan) and became a small employee in the local administration at an early age, but he was soon dismissed because he did not work very diligently. His step-mother later accompanied him to the capital where he entered the National University (taixue 太學). For more then ten years he dedicated himself to the study of the Confucian Classic Chunqiu 春秋 "Spring and Autumn Annals" before he qualified himself for appointment to court gentleman (lang 郞).
Under Emperor Cheng 漢成帝 (r. 33-7 BCE) he was made an erudite (boshi 博士) and later became regional inspector (cishi 刺史) of Shuofang 朔方 and then Censor-in-chief (yushi dafu 御史大夫). He was then appointed Counsellor-in-chief (chengxiang 丞相) and concurrently given the title of Marquis of Gaoling 高陵侯.
Zhai Fangjin was more then ten years the highest advisor of the emperor and proved to be a highly competent politician. Because of his educational background he was called the "classicist counsellor" (tongming xiang 通明相). In later years factional strifes in the imperial house and the arrest and death of his friend Wei Weichun 衛尉淳 made Zhai Fangjin feel uneasy. At the same time, natural disasters affected the empire, which gave Emperor Cheng an ideal excuse to charge Zhai of incompetence, and he was ordered to commit suicide.
His posthumous title is Marquis Gong 恭侯 (or Gong 共侯).