The Spanish side, fourth in La Liga and conquerors of Internazionale in the last round of the competition, were impressive throughout and led at the break thanks to a stunning David Silva strike.
The result means Valencia start next Tuesday's second leg at the Mestalla as slight favourites to reach the last four and a likely meeting with Liverpool.
In an all-action start to the game Valencia showed their intent as they stormed forward from the first whistle.
In the second minute Chelsea target David Villa's ambitious long-range drive drifted wide, while at the other end Ashley Cole charged down the left flank but a stretching Drogba was unable to latch on to the England international's cross.
In the tenth minute, after Andriy Shevchenko had dived theatrically looking for a penalty, the ball broke to Salomon Kalou who lashed a shot against the crossbar
Back came Valencia though, and after Villa had made space for himself down the left, he fired wide of Petr Cech's goal from a tight angle.
Valencia should have taken the lead midway through the first half when Joaquin's mis-hit shot went straight to the unmarked Silva inside the penalty area but he appeared to think he was offside and only contrived to deflect the ball wide.
Cech then clutched former Chelsea star Asier del Horno's dipping effort before Valencia took the lead on the half-hour mark in dramatic fashion.
There seemed little danger when Silva won the ball close to the halfway line, but he moved forward before unleashing a stunning 30-yard left-footed drive that flew past Cech before nestling in the back of the net.
On the stroke of half-time Santiago Canizares was caught in no-man's land from a free-kick, but Michael Ballack headed wide.
Immediately after the restart Kalou missed his shot at the far post after a great run and cross by Lassana Diarra before the erratic Canizares flapped at Frank Lampard's cross, but Chelsea are unable to capitalise on the keeper's error.
However, in the 53rd minute Canizares was not so fortunate when a hopeful long ball forward by Ashley Cole found Drogba, who headed the ball over the badly-positioned keeper who had strayed off his line.
Valencia regrouped after the goal though, and with Roberto Ayala dominant at the back, they restricted Chelsea to only a handful of half-chances.
Lampard fired wide from the edge of the penalty area on the hour and Ricardo Carvalho headed over the bar.
In a late flurry, Canizares struggled to deal with a corner and Shevchenko saw his overhead kick cleared off the line, but Valencia held on to a thoroughly deserved draw.