Karim Benzema's peerless exhibition of clinical marksmanship rescued the draw for a Real side muddled by a change of formation and the Blues' technical and tactical acumen.
Pulisic became the first man to score past former Chelsea stopper Thibaut Courtois in six hours and 44 minutes, as the Blues enjoyed a stellar opening.
Werner's flimsy finish allowed Courtois to produce a short-range save when the Germany forward should have powered into the net.
And the ex-RB Leipzig striker was unable to convert another big opening, failing to connect with Pulisic's cross at Madrid's Alfredo Di Stefano training ground stadium.
Chelsea will still occupy the box seat for the return leg at Stamford Bridge on Wednesday, May 5, with Thomas Tuchel's men producing another hugely impressive performance.
But despite boasting that potentially pivotal away goal, the west Londoners will be forgiven for wondering what might have been had Werner netted one or both of his prime chances.
Madrid paid the price for a quizzical switch to three at the back straight from the off.
Werner should have scored before the game had even settled, but instead he side-footed straight at Courtois.
Pulisic's unselfish header across goal begged to be blasted into the net, but Werner's tentative effort handed the ex-Chelsea keeper the chance to parry clear.
Pulisic was in no mood to waste an opening however, and his decisive strike put the Blues 1-0 up in the 14th minute.
Antonio Rudiger's sumptuous lofted ball caught Real out at the back, allowing Pulisic to spring whatever offside trap there was and power into the box.
The USA forward stayed calm as Courtois raced out, stepping round the keeper before powering home.
So poor were Madrid that Chelsea were able to canter into the final third almost at will once past the hosts' porous midfield three.
Benzema produced the first threat for Real however, thundering a 20-yard effort against a post.
And the French striker then conjured an equaliser of the highest quality just before the half hour, cushioning a header to himself six yards out – then flashing a snap volley past the helpless Edouard Mendy.
With Chelsea's scoreboard dominance cancelled out in one stellar moment, Tuchel's unperturbed men set about taking the game to Madrid once more.
Had Werner connected with Pulisic's teasing cross, Chelsea would have taken the lead again.
The Germany forward still found time to screw a shot wide of the near post when Mason Mount was lurking in the centre of the box.
And so the scores stayed locked at 1-1 at the break, with both sides showing signs of fatigue in a circumspect third quarter.
Marcelo's yellow card for a professional foul on the marauding Pulisic just past the hour allowed Madrid to send in ex-Chelsea talisman Hazard, on for Vinicius Junior.
Real switched to a back four for the closing 15 minutes and were almost caught out straight away, with Raphael Varane felling Havertz and earning a yellow card for his troubles.
Ziyech angled the resulting free-kick on goal, but Courtois comfortably gloved the effort.