He was born into a wealthy family in Wuxi. Ní Zàn was born after the death of the Kublai Khan, the Mongolian ruler who defeated the Song and established dominance over all that had traditionally been considered China. The Yuan rulers did not trust many of the Confucian scholars and instead preferred to instill Mongolians and Muslims to perform administrative tasks. Ní Zàn was born into an elite who could afford to be educated despite the unavailability of high-paying governmental jobs that traditionally were the reward for a rigorous Confucian education. These wealthy scholars and poets were often entertained by the eccentric Ní Zàn and were part of a movement that radically altered the traditional conceptions of Chinese painting. Their paintings depicted representations of natural settings that were highly localized, portraying personally valued vistas that reflected their individual feelings.
During the 1340s a number of droughts and floods caused a famine throughout Ní Zàn's region and subsequently lead to peasant revolts. These revolts reached a fever pitch in 1350 due to the government's use of forced labor to repair the dikes on the Yellow River. Throughout the 1340s, the Yuan imposed oppressive taxes on the rich landowners of the region in order to cover the cost of these natural disasters. There are many divergent opinions concerning Ní Zàn’s reaction to these taxes and his ensuing actions are unclear. However, it has been established that he distributed all of his possessions to his friends and moved into a houseboat. He left on the eve of the millenarianist Red Turban Revolt and traveled throughout the relatively peaceful southeast while various revolutionary parties tore through his region of origin. It was at this time that Ní Zàn developed his distinctive style.
Ni Zàn's landscapes after 1345 all take very much the same form: monochrome painting of widely separated riverbanks rendered in sketch brushwork and foreground trees silhouetted against the expanse of water. These sparse landscapes never represent people and defy many traditional concepts of Chinese painting. Many of his works hardly represent the natural settings they were intended to depict.