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The hosts needed late goals from Sergio Ramos and Karim Benzema to secure a two goal advantage ahead of next week's second leg in Catalonia.
Santiago Solari's side fell behind, as Girona threatened to spoil their party, after Anthony Lozano put them in front.
However Real were quick to respond, and Lucas Vàzquez netted his fourth goal of the season.
From there on, the home side dominated, and Ramos gave them the lead three minutes before half time from the spot - with a panenka finish past Gorka Iraizoz.
Girona found themselves an unexpected lifeline as Alex Granell scored from the spot.
But it was Ramos to the rescue again for Solari's side and then Benzema wrapped up the win three minutes later.
Girona will face an uphill battle in the second leg to reach their first ever Copa del Rey semi final.
