Setthathirat's military strategy in repelling Burmese invasions in 1565 and 1570 has preserved the autonomy of his kingdom.

A prolific builder, he has erected many Buddhist monuments including Wat Xieng Thong in Louang Phrabang and the That Luang in Vientiane.

A conspiracy in 1572 between a Lord Phya Nakhon and the former abbot of Wat Maximavat, who holds personal grudges against Setthathirath, leads to the murder of the thirty-eight-year-old king in the southern frontier of the country.

Because Setthathirath leaves only a toddler as his heir, the child's maternal grandfather, a military commander of common birth named Saensurin (or Sene Soulintha), declares himself king.

This begins a period of turbulence, with various men ruling unsteadily for short periods.