Niu Fen, style Fangpi, was a man from Ezuo county in Ju commandery in Xu province. His father, Niu Qi (牛愒), was a volunteer in the Yellow Scarves who later surrendered to the Han forces led by Zhu Jun (朱儁). His father became close friends with Zhu and even sent the young Niu Fen to live in Yangzhou with Zhu's son, Zhu Hao (朱皓).

When Sun Ce (孫策) invaded Liu You (劉繇), Fen, even though he was only fourteen sui at the time, served as a soldier in Zhu Hao's army. Later, Liu You and Zhu Hao were driven out of the commandery by Sun's forces, and Niu Fen accompanied them to the Yuzhang area. He engaged in battle with Yuan Shu's (袁術) official in the region, Zhuge Xuan (諸葛玄) and drove him out of the region. During that time, Zhu Hao's former ally Ze Rong (怎融) turned on him and killed him. Niu Fen took control of Zhu's former troops and launched a counterattack on Ze Rong, taking his head.

When Liu You died and his forces were absorbed by Sun Ce, Niu Fen surrendered. He found that his father had died in his home of Xiapi, so he requested to take his leave to fulfill his filial duties. Sun Ce agreed, and Fen took his leave. When he entered Xiapi, then under the control of Lü Bu (呂布), he was treated warmly by Lü Bu, who had become friends with Niu Qi during his rule. Niu Fen was honored by Lü Bu's warm reception and entered his staff. During that time, Lü Bu declared a ban on the consumption of alcohol. His officers, Hou Cheng (侯成), Song Xian (宋憲), and Wei Xu (魏續), had reclaimed several dozens of escaped horses and wished to celebrate. Hou Cheng was afraid to break the law, so he emptied all of the wine onto the ground.

Niu Fen was worried that Lü Bu would see the empty wine containers and think that the men had been imbibing, so he told Hou Cheng, "We need to make sure the wine is removed as well. Your robes should absorb the spilled wine." Hou Cheng thought the advice sound, so he, Wei Xu, and Song Xian began to roll on the ground to soak up the spilled wine. When Lü Bu entered the room, Hou Cheng, Wei Xu, and Song Xian smelled of alcohol, so he had them flogged. Thus, the three men came to despise Lü Bu.

Lü Bu was defeated by Cao Cao (曹操) shortly thereafter, and Hou Cheng, Song Xian, and Wei Xu all surrendered. Niu Fen managed to escape to the north, finding refuge with a sympathetic Yuan Shao (袁紹). He served in the battle of Guandu under Chunyu Qiong (淳于瓊) and guarded the Wuchao supply depot. He convinced Chunyu Qiong that he could turn the tide of battle by pretending to be inebriated so that Cao Cao's forces would attack the heavily defended supply depot. Chunyu Qiong thus pretended to drink himself into oblivion, but Niu Fen admonished him. "Cao Cao is a crafty man and has many able advisors. You will have to be more convincing than that." Thus, Niu Fen bade all of the men in Wuchao drink and be merry. He then came down with a sudden illness and withdrew to the latrine. When he came back, Wuchao was in flames, Chunyu Qiong was dead, and the depot had been seized by Cao's forces. With little alternative, he surrendered to Cao's army.

In Cao Cao's service, Niu Fen participated in the battle at Chibi as a naval commander. He suggested to Cao Cao that the boats be lubricated with cow fat so that they would move faster and that the boats be filled to the brim with hay for the horses to eat. Cao Cao accepted this advice despite the warnings of his advisors. After Zhou Yu (周瑜) burnt Cao's navy, Fen shed his armor, dove from the boat, and was picked up by navy of Liu Bei (劉備), who believed him to be an injured soldier of their own force, and thus followed Liu Bei from then on.

Fen made a name for himself in Liu's army and became close friends with Pang Tong (龐統), Liu's chief advisor. He warned Pang Tong, "Do not be too close to the rear of the army. If the enemy attacks from behind, you will be slain." Thus, Pang Tong was always at the front of his armies, often riding out several li ahead of his troops by himself. His death during battle against Liu Zhang (劉璋) surprised Fen, then stationed in Jingzhou, very much, and he cried bitterly. "If only Shiyuan had stayed in the vanguard, this could have been avoided!" he cried out.

Fen remained in Jingzhou under the command of Guan Yu (關羽) during the attack against Cao Ren (曹仁). Guan was worred about two of his officers, Mi Fang (靡方) and Fu Shiren (傅士仁). Both had been under a great deal of stress. Thus, Guan consulted Niu Fen for advice.

"Mi Fang and Fu Shiren love practical jokes," Fen suggested. "Pretend as if they are about to be punished after the campaign. Once we defeat Cao Ren, tell them that it was a joke, and their spirits will surely rise after they have a good laugh." Guan Yu consented to this advice. The battle against Cao Ren went poorly, however, and unexpectedly, Mi Fang and Fu Shiren defected to Lü Meng (呂蒙), the general sent by Sun Quan (孫權) to seize Jingzhou.

Guan was captured and executed by Sun's forces, and Fen, with little choice, surrendered. He was fearful for his life because he had abandoned Sun Ce over twenty years earlier, but the only person who recognized him was Jiang Qin (蔣欽), who was not one to hold a grudge. Thus, Niu Fen and Jiang Qin became close friends. Jiang fell ill, however, and knowing Niu Fen to be knowledgeable about medicine, asked his advice.

"Long-haired cats can cure many illnesses," Niu Fen suggested. Thus, he brought over a dozen long-haired cats and rubbed them on Jiang Qin's face. However, the treatment came too late, as Jiang started coughing and sneezing and soon died, much to Niu's dismay. He found that Lü Meng, suffering from the same illness at Jiang Qin, was in need of medical attention as well, so he brought the cats to Lü Meng's home and tried to save his life as well, but unfortunately, he was too late, and Lü had the same reaction as Jiang Qin.

Niu Fen feared for his life and plotted to defect to Shu during the battle of Yiling. He made contact with Liu Bei, stating that he would approach Liu's camp with a torch, and that this was his signal that the Wu army would be too weak to hold off an attack. Liu consented to the plan, and after a few initial victories against the demoralized Wu forces, he stationed himself at his camp and waited for Niu's signal.

Fen approached the Shu camp when the Wu forces were at their weakest, carrying the lit torch as had been the agreement. Suddenly, he heard Lu Xun (陸遜) and Sun Huan's (孫桓) armies approaching in a desperate attempt to push back Liu's forces, and frightened, he threw his torch at the Shu camp to avoid suspicion. The flames spread, and Liu Bei was soundly defeated. Lu Xun credited Niu Fen with the victory, and he was placed in the position of General of the Left.

Niu was incredibly long-lived and was well liked by Sun Quan. When Sun He (孫和) and Sun Ba (孫霸) fought for the position of Crown Prince, Fen suggested that Sun make Sun Liang (孫亮) the Crown Prince instead, thus giving He and Ba a common enemy to fight against. Sun agreed, but despite Niu's genius plan, Sun Ba became depressed that a mere child had been selected over him and committed suicide. Sun He was so distraught that he began beating his head on the floor. When his head became too sore to continue, he began banging the head of his young son, Sun Hao (孫皓), instead.

Niu served in the cabinets of Sun Liang and his successor, Sun Xiu (孫休). When Deng Ai (鄧艾) invaded Shu, Sun wanted to send Sun Yi (孫異) and Ding Feng (丁封) to aid Shu. Niu agreed, but added, "Shu is very cold this time of year. We should bundle the troops, generals, and horses in the thickest cloth and armor in order to avoid any losses due to the extreme weather." Thus, every soldier in Ding and Sun's units was ordered to wear seven robes instead of just one. Unfortunately, Ding and Sun were unable to arrive in time to save Shu, and Shu was annexed by Wei. Shortly thereafter, Sima Yan (司馬炎) overthrew Wei and became Emperor of Jin.

Sun Xiu died and was succeeded by his nephew, Sun Hao (孫皓). Niu Fen had been against the enthronement, instead suggesting that Sun Ce's grandson, Sun Feng (孫奉), be enthroned instead. Sun Hao agreed that Sun Feng would be a better emperor and offered to stand aside if Niu could bring Sun Feng, who had lived the life of a hermit for many years, into the imperial hall. Niu was able to convince Sun Feng to accept the throne, but on the eve of the ceremony, Feng, who had not seen a sword his entire life, became fascinated with Sun Hao's ceremonial sword. Hao offered his relative the sword to gaze upon, and Feng was so happy to receive the blade that he unsheathed it and started running around the court with it. He tripped, stabbed himself, and died. Sun Hao was so horrified and embarrassed on behalf of his relative that he requested Niu Fen to tell him what to do. Niu Fen suggested that rather than reporting Sun Feng's death as it had truly happened, Sun Hao should say that Sun Feng had been executed for a crime. Sun Hao consented to the advice.

During Jin's invasion of Wu, Niu Fen, despite being ninety-seven sui, bravely charged into the invading Jin armies alone. He cut down over a thousand men with his own blade before succumbing to the enemy's relentless attacks, and he died on the battlefield, his death taking place on the first day of the fourth month.