The Spaniard, who won the Premier League and FA Cup during his time with Arsenal, died in a traffic collision.
The news was confirmed by his former club Sevilla.
Lewandowski back in Bayern squad with title in touching distance
"We couldn't be announcing any worse news. Our beloved former youth player Jose Antonio Reyes has died in a traffic accident. Rest in peace," said a statement on Sevilla's official Twitter account.
Arsenal posted on their official website:
Our thoughts are with all his family, friends and team-mates. Jose, who was part of the Invincibles team, was a hugely popular figure at our club and will always hold a special place in our hearts. He represented the club on 110 occasions, scoring 23 times and made memorable contributions to our 49-game unbeaten run. Rest in peace, Jose.
Reyes joined Arsenal from Sevilla in January 2004 for a fee of £10.5m.
After making 110 appearances, scoring 23 goals, he had a loan spell with Real Madrid and then spent spells with Atletico Madrid, Benfica and Sevilla again.
He was most recently playing for Spanish club Extremadura having signed for the club in January.
Reyes won the Europa League five times during his playing career - amongst 20 major honours to his name.
He also won 21 caps for the Spanish national team. But of all his exploits across Europe, lifelong Sevilla fan Reyes still rated claiming silverware with his boyhood club as the most special.
Talking ahead of the 2014 Europa League final, in which Sevilla beat Benfica 4-2 on penalties, Reyes told orgullodenervion.com: “When I was small, I dreamt of winning a title with Sevilla.
Winning a title is the nicest thing there is. You feel something special, like you’ve done a really good job.
"It’s also great to see the fans so happy. In all the teams I’ve been at I’ve done very well. But Sevilla is my home."
Additional reporting: PA
Opinion: Ronaldo transfer could paper over cracks with United and their fans
Seville and St Petersburg handed Euro 2020 matches