Ex-Bayern Munich, Atletico Madrid and Juventus attacker Mandzukic, who was part of the Croatia side who finished runners-up at the 2018 World Cup, headed in a fifth-minute cross from Almoez Ali to give the hosts the lead at the Abdulla bin Khalifa Stadium in Doha.
Mandzukic got plenty of help from the Persepolis defenders though, as they were busy protesting an alleged foul even as Ali chipped the ball from just outside the penalty area.
Despite the early setback, the visitors, who boast a fan following of more than 40 million in Iran, failed to get their defence right as the home side consolidated the lead in the 13th minute.
North Korea forward Han Kwang-song took advantage of another Persepolis mistake by pouncing on a loose ball on the edge of the box before passing the ball to Brazilian Edmilson who scored with a low shot.
The Tehran side barely made an impact in the first half, but ex-Celtic striker Anthony Stokes tested the Al Duhail defence on his club debut a couple of times after the break.
In Group D, Qatars Al Sadd and Saudi Arabias Al Nassr figured in an entertaining 2-2 draw at the Prince Faisal bin Fahad Stadium in Riyadh.
Morocco forward Abderazzaq Hamdallah put the hosts ahead with a seventh minute strike from inside the box after a pass from Yahya al-Shehri as Xavis Al Sadd defence was found wanting.
The home side however only managed to hold on to the advantage for two minutes as Baghdad Bounedjahs crisp shot off a pass from Pedro Miguel helped Al Sadd draw level.
The second half also started on a similar note with both teams scoring inside the first 10 minutes, although it was Xavis side who took the lead this time, scoring in the 48th minute.
Miguel, who was born in Cape Verde but now is a naturalised Qatari, once again provided the assist, intercepting an attempted pass by al-Shehri before relaying the ball to Hassan al-Haydos, who made no mistake with a coolly taken shot past Australia goalkeeper Brad Jones.
The match was on level terms again five minutes later with Abdulrahman al-Obeid taking advantage of a loose clearance and finding the net with a powerful drive.
– Al Ain thrashed –
Earlier, in another Group D match, Irans Sepahan thrashed UAEs Al Ain 4-0 with three of the goals coming in the second half.
A 38th-minute header from Mohamed Mohebbi off Saeid Aghaeis cross put Sepahan ahead before strikes from Brazilian Kiros, Souroush Rafiei and Mohamed Tayebi completed the rout in what was the first clash between the two sides in the competition.
Al Ain, who won the tournament in 2003, were off colour despite playing in front of their home fans, missing several chances and giving away easy balls to their rivals at crucial moments.
There was further disappointment for a UAE side when Sharjah FC suffered a 1-0 home defeat against Saudi Arabias Al Taawoun in Group C.
A fine free-kick from Faisal Darwish in the 34th minute made all the difference as Al Taawoun won their first-ever away match in the tournament
Darwishs 30-yard screamer found the top corner of the net beating Sharjah goalkeeper Adil al-Hosanis desperate attempt at a save.
Former Croatia forward Mario Mandzukic struck on his Asian Champions League debut as Qatar giants Al Duhail beat… https://t.co/4YXU7Evkil
— Times of Malta (@TheTimesofMalta) February 11, 2020
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Al Taawoun could have won by a better margin but missed several chances in the second half.
In the East section an Ola Toivonen penalty ensured Melbourne Victory kicked off their campaign with a 1-0 over 10-man Chiangrai United from Thailand.
The opening clash between the other Group E teams, Beijing FC and FC Seoul, has been postponed until April due to fears about the spread of the deadly coronavirus.
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