The Catalans currently sit three points clear of their third-placed rivals in the Liga table and the 26-year-old feels that the Camp Nou clash could be pivotal in their defence of the Spanish title.
"It can mark a turning point in the season. If we win, we’ll be six points clear," he told the club's official website.
"The Clasico is a different kind of match and even more so this year because the title has been between the two teams over the last couple of seasons."
Pique went on to say that his side have found it harder to win games this season, citing Tuesday's 1-1 draw against Milan, whom he believed would be beaten comfortably.
“We’re leaving with a good feeling. I think in the end we lost a bit of perspective. We came to San Siro and we thought we were going to win 0-3 or 0-4,” he continued.
“Perhaps after winning so much over the years, not winning in the San Siro seems like a bad result, but we’re still the leaders of the league and of our Champions League group."