A Lionel Messi goal late in the first half earned Barca a 1-0 quarter-final second leg win in Ukraine, securing a 6-1 aggregate success that put the 2009 winners into the semis for a fourth consecutive season.
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Real, who defend a 4-0 lead against Tottenham Hotspur in London on Wednesday, almost certainly await in the last four.
The Spanish giants are set to clash four times in 18 days, including Saturday's La Liga match at the Bernabeu and the King's Cup final on April 20 in Valencia.
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Barca coach Pep Guardiola will again lock horns with his Real counterpart Jose Mourinho, a former Barca assistant who engineered Inter Milan's victory over the Catalan club in last season's semis and led the Italian side on to the title before moving to the Spanish capital.
"We are competing for everything with the most powerful club in the world of football," Guardiola said in an interview with Spanish television.
"Both are great teams and the pressure is the same for each," he added. "In the end it's a game and now we have to work out how we can cause them damage."
The temperature was hovering just above freezing at Shakhtar's imposing Donbass Arena as the home side set about what was always likely to be an impossible mission against Guardiola's slick side.
Despite Barca's comfortable 5-1 lead from last week's first leg at the Nou Camp, the former Spain and Barca midfielder had warned his players not to underestimate their opponents and he decided against resting any of his first-choice players.
Shakhtar enjoyed some decent early pressure and goalkeeper Victor Valdes was forced into saves from Douglas Costa and Jadson before the visitors began to get into their stride.
Argentina forward Messi squandered two decent chances before he broke the deadlock just before halftime.
Full-back Daniel Alves picked out the World Player of the Year in the penalty area and he held off three defenders before slotting low past Andriy Pyatov.
It was his ninth Champions League goal of the campaign, putting him top of the scoring chart, and a club record 48th of the season in all competitions - including a hat-trick against Sevilla in the Spanish Super Cup in August - beating the mark he set last term.
IN CONTROL
Barca were always in control of the tie and Pyatov denied Ibrahim Afellay with a brilliant one-handed save in the 59th minute before Guardi
