Espanyol took an early lead through former Manchester City forward Felipe Caicedo but Barcelona replied thanks to Lionel Messi’s first-half brace.
The Argentine talisman turned provider as he set-up Gerard Pique to put the hosts 3-1 up and Neymar added a late fourth to give Barcelona a commanding first-leg lead.
In a fiery encounter, referee Juan Martinez Munuera dished out 11 yellow cards and two red cards as both sides looked to claim bragging rights in the Catalan derby.
The home side handed summer signing Arda Turan his debut after the club’s transfer ban ended on Monday. Their other high-profile signing, full-back Aleix Vidal, started on the bench.
The next leg will be played next Wednesday at the Estadi Cornella-El Prat.
Meanwhile striker Alvaro Negredo scored a hat-trick, including two second half penalties, as Valencia thrashed Granada 4-0 in the first home leg of their Copa last 16 clash yesterday.
Negredo has been given a new lease of life under coach Gary Neville and the win was a confidence boost for Valencia who have yet to pick up a victory in La Liga under the former Manchester United and England player.
The derby clash between Real Betis and Sevilla finished with a 2-0 win for the guests, who head into the second leg with a healthy advantage as they look to qualify for the next round.
Michael Krohn-Dehli gave Sevilla the lead and Arsenal target Grzegorz Krychowiak doubled their lead.