The Saudi League side lost to Korea Republic's Ulsan Hyundai in the final at the end of last year, but continued their perfect start to the new continental campaign this season with an impressive 4-2 win over Sepahan in Iran last week.
And having already beaten both Al Gharafa and Al Nasr in Group C, Aleksander Ilic's side can secure qualification for the knockout stage for a second consecutive season by avoiding defeat at King Abdulaziz Sport City against the Iranian champions.
"We had a tough match against Sepahan as we had predicted," said Ilic, who took over from Karel Jarolim prior to the win over Al Nasr on Matchday Two, following the win at Foolad Shahr Stadium last week.
"The physical strength of the Sepahan players went down in the second half and we took a full advantage from that to gain victory. We knew that Sepahan had played three days ago against Esteghlal in a hard encounter and we also knew that they were going to have issues with their physical fitness.
"But I respect Sepahan and I believe that they will play better football in Jeddah."
Al Ahli, though, will be without Victor Simoes due to suspension after the Brazilian striker scored twice in Tehran last week but also collected a second yellow card of the group stage.
And while Al Ahli took a break from domestic action following the win in Tehran, Sepahan bounced back by returning to the top of the Iran Pro League by extending their domestic win streak to five games with a 3-1 win over Naft Tehran on Saturday.
Also in Group C on Wednesday, play-off winners Al Nasr travel to Doha to face second place Al Gharafa with the UAE Pro League side needing to win to avoid elimination.
Al Nasr trailed by three goals at half-time in Dubai last week and despite scoring twice at the start of the second half, Walter Zenga's side fell short of avoiding a third consecutive defeat as Al Gharafa struck a decisive late blow to claim a 4-2 win.
And Zenga will still be without captain Leonardo Lima after the Brazilian midfielder was sent-off in the first half of the 2-1 defeat by Al Ahli last month.
Elsewhere, unbeaten Saudi champions Al Shabab can secure passage from Group A with victory over Iran's Tractorsazi in Tabriz should winless Al Jazira also fail to beat Qatar's El Jaish.
Al Shabab extended their unbeaten start to the campaign with a 1-0 win over debutants Tractorsazi in Riyadh last week, while El Jaish picked up their first win of the campaign after beating Al Jazira 3-1 in Doha.
And Al Jazira, who reached the last 16 for the first time in four attempts last year, know a repeat of last week's result could end their campaign should Al Shabab avoid defeat against Tractorsazi.
In the East, joint Group G leaders Beijing Guoan and Bunyodkor meet in China, while fellow table-toppers Pohang Steelers entertain Sanfrecce Hiroshima with the J.League champions in desperate need of their first points of the campaign.
After Beijing shared a goalless draw in Tashkent last week and former champions Pohang claimed a 1-0 win in Japan, all three teams top the table with five points with Sanfrecce adrift at the foot of the table after suffering a third consecutive defeat.
Should Sanfrecce lose to Pohang and either Beijing or Bunyodkor win at Workers' Stadium, Sanfrecce' s maiden AFC Champions League campaign will come to an end.
Beijing, though, will be without Ecuadorian midfielder Joffre Guerron due to suspension.
Finally, Group E leaders FC Seoul travel to Japan to face Vegalta Sendai, while Thailand's Buriram United entertain China's Jiangsu Sainty.
K-League champions FC Seoul moved three points clear at the top of the table after extending their unbeaten record with a 2-1 win over Sendai last week, while Jiangsu picked up their first win of the campaign after recording a 2-0 win over Buriram.
And should Buriram fail to beat Jiangsu, FC Seoul can secure qualification to the Round of 16 with a third win of the campaign on Wednesday.
Buriram coach Atthaphol Puspakom will be without defender Suree Sukha and midfielder Anawin Jujeen, who was sent-off last week, due to suspension.
Wednesday's AFC Champions League Fixtures
Al Jazira vs El Jaish
Tractorsazi vs Al Shabab
Al Gharafa vs Al Nasr
Al Ahli vs Sepahan
Vegalta Sendai vs FC Seoul
Buriram United vs Jiangsu Sainty
Pohang Steelers vs Sanfrecce Hiroshima
Beijing Guoan vs Bunyodkor