Setthathirath is considered one of the great leaders in Lao history. In 1570, he successfully defended Laos against the military campaign of the Burmese conqueror Bayinnaung , who had already subdued Xieng Mai (Chiang Mai) in 1556 and Ayutthaya in 1569. Setthathirath was a prolific builder and erected many Buddhist monuments including Wat Xieng Thong in Louang Phrabang and the That Luang in Vientiane. In 1572, a conspiracy between a Lord Phya Nakhon and the former abbot of Wat Maximavat, who held personal grudges against Setthathirath, led to the king's murder in the southern frontier of the country. He was 38 years of age.

Because Setthathirath left only a toddler as his heir, the child's maternal grandfather, a military commander of common birth named Saensurin (or Sene Soulintha ), declared himself king. This began a period of turbulence, with different men ruling unsteadily for short periods, which saw the country finally conquered by Bayinnaung (the Burmese would rule Laos for eighteen years); with a fratricide by a crown prince; with a rebellion led by someone claiming to be Setthathirath-resurrected; and with a nine-year period in which the country had no king. Selfish quarrels and conflicts among the feudal nobility and their followings led to disruptions and unrest within the population. There was little peace in Laos until King Sourigna Vongsa ascended the throne in 1633 (possibly 1637).