The Brazilian former Indycar racer - de Ferran twice won the CART title as well as the Indianapolis 500 in 2003 - joined the team in April 2005.
But, having decided that the job had not matched up to his initial hopes, the 39-year-old has left the team to "pursue other opportunities".
"I am obviously very disappointed to be leaving the Honda F1 team," de Ferran said in a team statement. "I have a huge amount of respect and admiration for Honda, with whom I have been successfully associated for more than 10 years.
"Consequently, my decision to leave has not been an easy one. I simply feel that I came to this team to fulfil a particular role and it has not materialised as I had hoped.
"I would like to thank everyone at the team for the support I have been given and I wish them luck in the future."
De Ferran's departure comes less than a year after Jenson Button claimed the contemporary Honda team's maiden victory in the Hungarian Grand Prix, the Englishman then ending the season strongly with a string of points-paying finishes.
But Honda have suffered a dramatic reversal of fortune this season, with Button taking their only championship point thus far in the recent French Grand Prix.
Honda team principal Nick Fry added: "I am disappointed that Gil is leaving our team. Since he joined us in 2005 we have enjoyed a very positive relationship.
"However, a Formula One team is rather like a jigsaw puzzle in that every piece has to fit precisely in its place.
"Gil has become increasingly uncomfortable in his role and feels the time has now come to seek fresh opportunities.
"We are very much hoping that Gil will choose to maintain close links with the Honda family."
