Following the reign of Tilokkarat, the Lan Na kingdom faced internal princely disputes that weakened its ability to defend against rising neighboring powers. The Shans, once under Lan Na's control established by Tilokkarat, gained independence. Paya Kaew, Tilokkarat's great-grandson and one of the last strong rulers of Lan Na, attempted to invade Ayutthaya in 1507 but was repelled. By 1513, Ayutthaya's Ramathibodi II sacked Lampang, and in 1523, Lan Na lost its influence in Kengtung State due to a power struggle.

King Ketklao, Kaew's son, faced turbulence during his reign. He was overthrown by his son Thau Sai Kam in 1538, restored in 1543, but faced mental challenges and was executed by 1545. His daughter, Chiraprapha, succeeded him. However, with Lan Na weakened by internal strife, both Ayutthaya and the Burmese saw opportunities for conquest. Chiraprapha was eventually forced to make Lan Na a tributary state of Ayutthaya after multiple invasions.

In 1546, Chiraprapha abdicated, and Prince Chaiyasettha of Lan Xang became the ruler, marking a period where Lan Na was governed by a Laotian king. After moving the revered Emerald Buddha from Chiangmai to Luang Prabang, Chaiyasettha returned to Lan Xang. The Lan Na throne then went to Mekuti, a Shan leader related to Mangrai. His reign was controversial, as many believed he disregarded key Lan Na traditions. The kingdom's decline was characterized by both internal disputes and external pressures, leading to its diminished power and influence in the region.