The Argentina international failed to make the grade in North London following his arrival in 2019, initially on loan before his stay was made permanent at the end of that season.
With Lo Celso's Tottenham deal due to expire in 2025, the midfielder was always expected to complete a transfer elsewhere this summer, and Spurs have now announced his return to La Liga.
The Lilywhites - who were initially struggling to agree a deal with their Spanish counterparts - will reportedly receive €10m (£8.4m) for the sale of Lo Celso, in addition to add-ons and an unspecified sell-on clause.
The 28-year-old heads for the Tottenham exit door after racking up 10 goals and eight assists in 108 matches for the club across all tournaments, also spending time on loan with Villarreal while contracted to Spurs.
While playing for the Yellow Submarine, Lo Celso helped the Spanish outfit reach the semi-finals of the 2021-22 Champions League, and he has also been a part of Argentina's two Copa America-winning squads.