Naif Hazazi struck twice as the Jeddah-based club - winners of the competition in 2004 and 2005 - mounted an astonishing fight back to leave Marcello Lippi's Guangzhou needing to win by at least two clear goals in the return match at Tianhe Stadium on October 2 to have any chance of progressing to the last four on their maiden appearance in the competition.
Gao Lin had given the Chinese Super League champions the lead after 27 minutes only for Diego De Souza to level for Al Ittihad less than a minute later.
Huang Bowen restored Guangzhou's lead six minutes before the break, but after a Mohammad Noor penalty four minutes after the resumption levelled the scores once again, a pair of headers from Hazazi - in the 62nd and 89th minutes - sealed the win for Al Ittihad
"I think in the second half we showed our heart and soul by taking the ball constantly," said Al Ittihad's Spanish coach Raul Caneda.
"In the second half they suffered and when we scored the second goal we were playing well.
"But we tried to take control of the ball. They are a top team with top players from around the world, but when they didn't have the ball they suffered.
"The things I said to the players this week I repeated to them before the game and at half-time, and that was if we have control we can make them suffer and if they have control they can make us suffer.
"This was a game in which they would suffer or we would. And the difference was who would take the ball."
Despite the defeat, World Cup winning coach Lippi remained hopeful tournament debutants Guangzhou can bounce back on home soil.
"We lost Muriqui due to injury and some of our players were only at 50% and hadn't fully recovered and also we had some errors which weren't supposed to happen and that's why we lost," he said.
"But this game will be decided over 180 minutes and hopefully when we play at home all of our players will be back."
Ulsan Hyundai, meanwhile, maintained the hopes of Korea Republic in the AFC Champions League by taking a 1-0 advantage into the second leg of their quarter-final against Saudi Arabia's Al Hilal.
Newly acquired Brazilian striker Rafinha scored the only goal after 10 minutes as Ulsan seek to become the fourth Korean club in four years to reach the final of the continental championship.
"It was an important game for both teams and we did very well," said Ulsan coach Kim Ho-gon.
"The players did very well and we are in a good position in the AFC Champions League. We will now look to prepare well for next game and qualify for the next round."
In Adelaide, Uzbekistan champions Bunyodkor fought back from a poor start to draw 2-2 with Australia's Adelaide United at Hindmarsh Stadium, leaving their quarter-final evenly poised going into the second leg in Tashkent on October 3.
Iain Ramsey and Evan Kostopoulos gave Adelaide a two-goal lead as the Tashkent-based club made a sluggish start, but Nigel Boogard's sending off was quickly followed by Jasur Khasanov halving the deficit and Shavkat Salomov struck 15 minutes from time to earn Bunyodkor a well-deserved draw.
"It was a very interesting game because today [Wednesday] was the first time that I saw Adelaide play a very aggressive attacking game," said Bunyodkor coach Mirdjalal Kasimov.
"When they scored their first goal, it was a real shock to us and my players started feeling uncomfortable. They started very well and for the first 20 minutes we were found it very difficult to play against them.
"But after we had got over the shock, we managed to recuperate and controlled the ball. Of course, the red card to their defender helped us."
Finally, former AFC Champions League finalists Sepahan - who lost in the deciding game of the 2007 edition to Japan's Urawa Reds - were held to a 0-0 draw by Al Ahli, the third of Saudi Arabia's participants in the quarter-finals.
Both sides squandered a host of chances and the result means Al Ahli will be favourites to progress to the semi-finals, where they could meet cross-Jeddah rivals Al Ittihad.
However, Al Ahli coach Karel Jarolim is taking nothing for granted ahead of the second leg in Jeddah on October 2.
"It's natural that Sepahan wanted to win tonight's [Wednesday] game, just like us," said Jarolim. "But in the next match we'll be playing in front of our fans and we will be trying hard to wrap up the victory at home.
"However, a 0-0 draw doesn't guarantee anything for us and we need to put in our best effort to write our own fate when we go head-to-head with them at home."