The German forward joined Chelsea from Leipzig in the summer of 2020.
Werner scored 23 times in 89 appearances across all competitions for Chelsea and won the Champions League in his first season.
Leipzig have reportedly paid €30m (£25m) to sign the Germany international.
Werner, who will wear No.11 for Leipzig, told Leipzig's website: "I'm very happy to be able to play for RB Leipzig again. I had a great time here between 2016 and 2020, when we performed brilliantly as newcomers in the league.
"It was a dignified departure for me to leave the club as record goal scorer, but that's in the past now and I'm looking ahead, because both I and the club have developed in the past two years.
I had two great years at Chelsea that I'm really grateful for and were crowned with the Champions League trophy. The experience to play abroad in a new league really helped me and my career.
"Now I'm looking forward to the new season with RB Leipzig and above all to meeting the Leipzig fans again, who mean a great deal to me. We want to achieve a lot and of course, I want to become the first Leipzig player to reach the 100-goal mark."