The Saudis finished bottom of Group H with two points and were eliminated after drawing with both Uruguay and Cape Verde and losing to Spain.
"The national team's failure to qualify for the next round of the World Cup is a result that falls short of all our ambitions," Al-Misehal wrote on social media.
"I bear full responsibility for it, apologising to everyone who hoped to see our team in a better position.
"Based on my conviction that responsibility requires providing the opportunity for a new phase, I have decided not to continue until the end of the current term."
Al-Misehal had been in the role for seven years and was heavily involved in Saudi Arabia's successful bid to win the hosting rights for the 2034 World Cup.
Saudi Arabia were appearing at their third consecutive World Cup and seventh in total but their preparations were hit by the decision to replace Herve Renard with Georgios Donis less than two months before the tournament kicked off.
The results come after the government had poured huge sums in the sport over recent years, with Saudi clubs signing high-profile players including Cristiano Ronaldo and Neymar Junior in an effort to boost standards within the country.
FIFA World Cup 2026
The 2026 World Cup took place from June 11th to July 19th in the United States, Canada and Mexico. The tournament featured 48 national teams and was won by Spain, who beat Argentina in the final.
Full schedule and results | Group standings and bracket | Past winners of the tournament | Our team of the tournament | About the 2030 World Cup