Cannondale rider De Marchi went clear 12 kilometres from the finish in the southern town of Alcaudete on Friday to claim his first Grand Tour stage triumph.
The Italian had been part of a four-man breakaway with Ryder Hesjedal (Garmin-Sharp), Johann Tschopp (IAM Cycling) and Hubert Dupont (Ag2r-La Mondiale) that surged ahead of the pack 40 kilometres after the start of racing in Alhendin.
The quartet appeared set to contest a frantic finish, but events turned in De Marchi's favour 15 kilometres from the line as Dupont fell off the pace on a short ascent before Hesjedal crashed on a left-hand bend.
That allowed De Marchi to accelerate away from Tschopp and secure a first success since winning the final stage of the 2013 Criterium du Dauphine.
De Marchi said: "It's the best memory of my career. It was great to be in a break with such strong riders. This clearly is my best result. It was a near-perfect day for me."
On one of the events flatter routes, the general classification contenders may have been forgiven for preserving their energy ahead of Sunday's stage-nine summit finish.
However, 2013 Tour de France winner Chris Froome had other ideas.
The British Team Sky rider had crashed on the first of the stage's two categorised climbs, but recovered to rejoin the peloton before gaining three seconds on Valverde (Movistar) with a determined late surge.
Froome is now 19 seconds adrift of home hope Valverde in fourth as the overall leader finished in the pack to stay 15 seconds ahead of team-mate Nairo Quintana, with two-time Tour de France winner Alberto Contador (Tinkoff-Saxo) three seconds further back.