Barca build huge lead on Real Madrid in Women's Champions League quarters
Pere Romeu's side, who have dominated the competition in recent years, moved two goals ahead through Ewa Pajor and Esmee Brugts inside 13 minutes.
Linda Caicedo pulled one back for hosts Real Madrid at the Alfredo Di Stefano stadium but Irene Paredes quickly restored Barca's two-goal lead.
Pajor and Vicky Lopez netted in the second half before Caicedo struck again for Madrid to give them some faint hope. Alexia Putellas added a late penalty to leave the Catalans with one foot firmly in the semi-finals.
Barca, now unbeaten in their last 25 games across all competitions, finished runners-up to Arsenal last season.
The three-time winners have reached five straight finals and are on the brink of an eighth consecutive semi-final, without injured three-time Ballon d'Or winner Aitana Bonmati.
Instead it was two-time winner Putellas who created the opener for Barca's top scorer Pajor.
Patri Guijarro's clever dink over the top allowed Putellas to square for Pajor to stab her fifth Champions League goal this season into an empty net.
Lopez's looping cross was met by Brugts for Barca's second, with Madrid goalkeeper Misa Rodriguez pushing the ball into the air but it dropped down and over the line, with defender Maelle Lakrar unable to keep it out.
Pajor should have extended Barca's lead but, through on goal, took the ball too close to Rodriguez who managed to knock it to safety.
A few minutes later Pau Quesada's Madrid pulled one back through Caicedo, who got in behind Barca's defence, rounded goalkeeper Cata Coll and fired home.
Madrid's happiness was short-lived as two minutes later Paredes restored Barca's advantage with a towering header from a corner.
Polish striker Pajor netted her second with a cool finish before the hour mark when 18-year-old midfielder Clara Serrajordi sent her through on goal.
Lopez added the fifth with a low finish from Caroline Graham Hansen's cut-back as Barca humiliated their rivals.
The Catalans have won all four matches they have played against Real Madrid this season, scoring 16 goals to Madrid's two.
The bad news for Madrid is that they have to face Barca again in Liga F at the weekend, before the second leg next week, with this the first of three Clasicos in nine days.
The good news is that Barca seem to have no answer to Colombian attacker Caicedo, who curled into the top corner from the edge of the box to pull another one back for the hosts.
Putellas converted from the penalty spot late on after Hansen was felled to round off the rout and minimise Madrid's chances of a comeback.
Madrid, who have never reached the semi-finals before, will have to record only a second ever victory against Barca to progress, with the Catalans winning 22 of their 23 encounters to date.