Hessenthaler, who has agreed a two-year deal, had two spells as Gills boss and was in joint caretaker charge of the League One side earlier this season.
Hendon played alongside the 49-year-old at Barnet and was his assistant at Priestfield during the 2010-11 season.
"I am delighted to have someone with Andy's experience and knowledge by my side," Hendon told the club website.
"I have worked with him and he is a very good coach. I also played alongside Andy in the same team and know what attributes he will bring to the club.
"Andy will work alongside Kevin Nugent, who remains very much part of my coaching team."
Hessenthaler made over 360 appearances for Gillingham during a stint with the Kent club which spanned a decade and included a period as player-boss.
He returned as manager in 2010, but stepped down two years later before becoming director of football, only to leave the club in May 2013.
He was appointed as assistant manager by Peter Taylor last summer and remained part of the coaching set-up after Justin Edinburgh was appointed boss in February.
Hessenthaler described the move to Orient as "an incredibly difficult decision".
He added: "I've had a 20-year relationship with Gillingham and I love the club. However, I felt it's a fresh challenge for me and I look forward to what lies ahead."
Former West Ham coach Hendon was appointed O's manager in May on a two-year deal, following their relegation to League Two.
Leyton Orient boss Ian Hendon has appointed Gillingham's Andy Hessenthaler as his assistant manager.