Padalecki is taking a break but will begin shooting the 11th season of the CW series in July as scheduled, his reps said in a statement.
Hints of the star's troubles first surfaced Friday night, when he tweeted, "Dear #JIBCON and #AHBL6. I am in desperate and urgent need of my family. I am so sorry to tell you this but I must head home."
Padalecki then pleaded for support from his 2 million Twitter followers: "I need all of the love I can get right now. Please please give me a few seconds of your time and write me."
He included the hashtag "#AlwaysKeepFighting," referring to a charity
he recently founded for those, including himself, who suffer from depression.
Along with Jensen Ackles, Padalecki is the co-star of "Supernatural," a fantasy drama about two brothers who hunt down demons, ghosts and other monsters. The show's fanbase is extremely devoted, and it's a big reason why the long-running CW series is entering its 11th season in the fall.
Padalecki, 32, also was a regular on "Gilmore Girls" and has appeared in several horror movies.
His tweets had led some fans to ask what was going on and lend their support.
His co-star, Jensen Ackles, also lent his support, along with other members of the cast.
Representatives for Padalecki sent this statement to CNN late Sunday:
"Jared wanted everyone to know he loves meeting his fans around the world and was very upset at having to cancel his trips to Rome and Australia. Jared has pushed himself to his limits and is suffering from exhaustion. His SPN family is so important to him, and he asks that they Always Keep Fighting. At this time he needs to be home with his family. He's doing better already and is excited about shooting 'Supernatural' season 11 this July. For now he's taking a break, but is so appreciative of his fans, and sees and feels their love and support."