The 20-year-old England youth international joined Tottenham from Fulham for £15m at the start of last season.
Sessegnon had to wait until November to make his Spurs debut because of injury and went on to feature 12 times in all competitions, scoring his only goal against Bayern Munich in the UEFA Champions League.
Sessegnon has not appeared in any game for Tottenham in the current campaign, having been pushed down the pecking order at left back by Ben Davies and summer signing Sergio Reguilon.
Hoffenheim, who will be playing Europa League football, are sixth in the Bundesliga after six games.
Sessegnon will be hoping to become the latest young Englishman to excel in the German top flight, with the likes of Jadon Sancho and Reiss Nelson as reference.
"Hoffenheim stands for the successful training and development of young players," said Sessegnon in a statement.
"I hope that the move will give me match experience in one of the best professional leagues in the world and I'm looking forward to playing in Europe."
Hoffenheim director of football Alexander Rosen added: "Ryan Sessegnon is a very talented and fast winger with a strong left foot.
"After the serious injuries suffered by Ermin [Bicakcic] and Stafy [Konstantinos Stafylidis], both of whom will not be available for several months, we were looking for a high-quality addition to our squad and are very happy to have found one in Ryan."
