Starting the day two shots off the lead following his opening 64 at the Real Club de Golf Sotogrande in southern Spain, Campillo took over at the top after just two holes on Friday courtesy of a hole-out eagle from the 11th fairway.
And he never looked back, adding five birdies to reach 15 under and take a commanding lead into the weekend.
England's Dan Brown was Campillo's nearest challenger at 11 under after following up his first-round 63 with a 70 in round two.
Spanish two-time major winner and Ryder Cup star Jon Rahm will be one to watch over the weekend after shooting a second-round 66 to sit in a tie for sixth on eight under.
The world No.14 is the top-ranked player in the field this week, which marks the final tournament of the year on European soil for the European tour.
The remaining events are in South Korea and the UAE. The only other top 50 player in the world is South Africa's Thriston Lawrence (70), who sits at five under.
Campillo is a three-time DP World Tour winner but none of his previous victories have come in Europe and he is hoping to change that this week.
Speaking from the commentary box after finishing his round, the 38-year-old said: "It would be nice. I have never won in Europe, always in Africa or Asia. Yeah, it would be great, definitely.
"Still a lot to go but it would be nice to win in your home country."
On his fine start, Campillo added: "I made a good putt on 10 to save par and then the eagle on 11 was a great way to set the tone.
"It was a tough pitch shot but that's the best part of my game. I hit it perfectly and it went in the hole, which was nice."
With AAP.
