After making his final appearance at Cam Nou in Barca's 2-0 win over Almeira last weekend, the 35-year-old defender was an unused substitute against Osasuna as the Catalan giants secured their fifth successive La Liga victory.
Pique received his marching orders after arguing with referee Jesus Gil Manzano as both teams walked down the tunnel at half time - an incident which capped off a lively first 45 minutes at the Estadio El Sadar.
Barcelona went behind in the sixth minute when Osasuna's David Garcia headed into the bottom corner following an out-swinging corner from Ruben Garcia.
Osasuna's hopes of securing a famous win over the Catalan club were then boosted when Robert Lewandowski was sent off for two bookable offences within the first 31 minutes.
After picking up an early yellow card for a full on Ignacio Vidal, Lewandowski received his second booking for barging into David Garcia, with his elbow colliding into the Osasuna winger's face.
Barcelona went into the interval a goal behind and Pique was left angered by the referee's decision to dismiss Lewandowski before receiving his own red card after the half-time whistle blew.
The veteran defender has now joined an exclusive club along with Pep Guardiola and Hristo Stoichkov in receiving the most red cards (eight) for Barcelona in La Liga history.
Pique and Lewandowski were unable to help out their teammates in the second half, but Xavi's side managed to cope without the experienced pair as goals from Pedri and Raphinha turned the game on its head.
Barcelona came out the blocks quickly and restored parity just three minutes after the break when Pedri pounced on to a loose ball inside the penalty area and fired his effort into the bottom corner.
Marc-Andre ter Stegen was called into action in the 70th minute when he tipped Ezequiel Avila's audacious curling effort from the far left side of the pitch over the crossbar.
Barcelona continued to push for the winner with 10 men, and their pressure in the final third eventually paid off five minutes from time when Frenkie de Jong played a delightful floated ball over the Osasuna defence to pick out the run of Raphinha, who looped a header from the edge of the area over goalkeeper Aitor Fernandez.
After Real Madrid suffered a surprise 3-2 defeat against Ray Vallecano on Monday, Xavi's side have now moved five points clear at the top of La Liga.
Barcelona's next game will be after the 2022 World Cup when they face Espanyol at Camp Non on New Year's Eve.