Zhu Houcong, a cousin of the Zhengde Emperor, was made the new emperor as the puppet of Zhang Yong and the Eight Tigers. His disdain for the duties of an Emperor was perfect for the Tigers, as they would rule in his stead, making important decisions while he spent his time in brothels and private palaces.
In 1524, tired of the Chinese Assassins' meddling, the Eight Tigers triggered the Great Rites Controversy which led to the Jiajing Emperor hunting down many officials to destroy all who opposed him. As a byproduct of this, the entire Chinese Assassin branch was almost eradicated, with only a few survivors fleeing west to seek support from other Assassins.
To prevent them from succeeding, the Jiajing Emperor sent men after them, following the Assassins as far as Italy. In Venice, they killed the Chinese Mentor Zhu Jiuyuan, who was traveling with a female Assassin named Shao Jun, who managed to escape them. They followed her to Florence, where she sought aid from the former Mentor of the Italian Assassins, Ezio Auditore da Firenze, to learn how to rebuild the Chinese Brotherhood. The Jiajing Emperor's men tracked the two to a marketplace in Florence while Ezio ran errands, and one of the men confronted them in an alley.
Shao fought and killed him, and both she and Ezio quickly fled, knowing more of the Jiajing Emperor's men would most likely follow. On the carriage ride back to Ezio's home, Shao told him about the Jiajing Emperor's cruel ways. She explained that the Jiajing Emperor liked to inflict pain on his enemies with torturous deaths. Explaining that she had been a concubine before her mentor Wang Yangming had saved her, but when they returned to save the other concubines, the Jiajing Emperor had killed them all via líng chí: a slow process of a thousand cuts until death.
Later that night, the rest of the Jiajing Emperor's men faced both Ezio and Shao at Ezio's house. Most of the men employed Chinese sword-fighting techniques, but one of them instead used a Chinese hand cannon. Though they fought well, the men were all killed by the two Assassins. The next day, Shao departed for China, but not before receiving a mysterious gift from Ezio—a tiny chest, which he told her to only open if she lost her way.
From 1542 to 1550, the Emperor's empire was harassed by the Mongol leader Altan Khan. The Jiajing Emperor ended the conflict by offering the Mongol leader special trading rights. After the end of the conflict, the emperor expanded Peking by building the Outer City.
In his later years, the Jiajing Emperor developed an interest in alchemy and immortality drugs. In 1567, Shao Jun, playing on his desire to find the elixir of life, presented him with what she claimed was the miraculous concoction. The Emperor foolishly believed her and ingested the gift, which was actually concentrated mercury, and promptly succumbed to mercury poisoning, finalizing Jun's vengance. 
- A message that Clay Kaczmarek wrote in blood on the wall in Desmond Miles' room stated that "Within Emperor Jiajing's sin and Quetzalcoatl's hunger lies the answers."
- The Jiajing Emperor's birth name is Zhū Hòucōng (朱厚熜). His family name, Zhū (朱), refers to the color vermilion. Hòucōng (厚熜) is his personal name. The former component Hòu (厚) literally means "thick" though in the context of a name can mean "profound" and "substantial". Cōng (熜) is an archaic word for "chimney" and thus taken together, his name literally means "thick chimney" though it is likely to have a figurative meaning.
- Jiājìng (嘉靖) is Zhū Hòucōng's era name. Historically, Chinese emperors were given posthumous names, temple names, and era names. The former two were given only after death, and while living, the emperor would only be known as "the Emperor" or "his imperial majesty" to all but his close friends and relatives. In English, it is conventional to refer to early Chinese monarchs by their posthumous names. However, after the Tang dynasty, posthumous names became increasingly long and tedious to read and write, spanning at least seven characters. From the Tang up until the Mongol Yuan dynasty, emperors are conventionally referred to by their temple names, whereas the emperors of the last two dynasties, the Ming and Qing, are commonly referred to by their era names. Emperors of dynasties before the Ming tended to have multiple era names, which made it impractical to adopt their era names to identify them posthumously, but starting from the Ming, emperors began to adopt one era name per reign.
- As Zhū Hòucōng's era name, Jiājìng is not one of his actual names, but the name of his regnal years. Thus, it is incorrect to call him "Emperor Jiajing" or even "Jiajing" rather than "the Jiajing Emperor" (i.e. "Emperor of the Jiajing era"). This mistake is repeated several times in the database entries and documents of Assassin's Creed Chronicles: China.
- In the era name Jiājìng (嘉靖), the first component jiā (嘉靖) means "excellent", "auspicious," "favorable" while jìng (靖) describes an environment that is calm, quiet, and peaceful. Era names were chosen to reflect what the emperor's court desired of his reign upon his ascendance but did not necessarily reflect its actual course.