Barca, the 2009 winners, thumped Arsenal 6-3 in last year's quarter-finals, drawing 2-2 in London before Lionel Messi scored all four goals in a 4-1 comeback win at the Nou Camp.
The teams also met in the 2006 final, when 10-man Arsenal took a first-half lead at the Stade de France in Paris before Barca fought back to win 2-1.
The Catalan club's vice president Javier Faus told Reuters the presence of seven Spanish World Cup winners and World Player of the Year Messi in the Barca squad was grounds for optimism.
"Having said that, Arsenal are an extremely strong team and in my opinion the one that plays the best football in the English league," Faus said in an interview.
"They are well placed in the Premier League and it's going to be a very tough tie."
Wednesday's other last-16, first leg pits Serie A side AS Roma against Ukraine's Shakhtar Donetsk, who are appearing in the last 16 for the first time after failing in five previous qualifying attempts.
Roma have not won in three domestic league games and fans protested at training after Saturday's 2-0 home defeat by Napoli which left last season's runners-up in eighth.
There have also been off-field distractions.
An American consortium was given a 30-day exclusive negotiation period on Tuesday to discuss a purchase of the cash-strapped club and media reports have said coach Claudio Ranieri's job could be under threat.
"This match could be a good medicine for Roma and we will do our best," defender Philippe Mexes said.
