Adelaide host the first leg at Hindmarsh Stadium before making the long trip to Tashkent two weeks later having already edged out Bunyodkor en route to the 2008 final before also having the edge over the Swallows in the Group Stage this year.
"Obviously the first game is at home and depending on that score, we're going to have to go away and battle to get through," said Adelaide captain Eugene Galekovic.
"It's going to be tough going over to Tashkent, but we're looking to get a result at home first and then go from there."
Adelaide beat Bunyodkor 3-1 on aggregate during the 2008 semi-finals after winning 3-0 at home in the first leg and the Reds then also had the edge over Mirdjalal Kasimov's side this time around after winning 2-1 in Uzbekistan during the Group Stage before the pair shared a goalless draw in the return fixture.
And with the new A-League season not starting until after the second leg in Tashkent, Adelaide have enjoyed a solid pre-season campaign since overcoming Japan's Nagoya Grampus in the last 16 at the end of May.
The Reds have named a largely unchanged squad for the knockout phase of the AFC Champions League, although coach John Kosmina was forced into a late change with Jeronimo Neumann replacing fellow Argentinian import Marcelo Carrusca.
Carrusca was named in the initial squad, but after struggling with a calf injury recently, Kosmina opted to draft in Neumann who has featured in a number of Adelaide's recent pre-season outings after both players arrived during the closed season.
"It's going to be another tough two games," said Galekovic, who has kept five clean sheets in the AFC Champions League this season having kept six in 2008.
"They're going to be a lot better than when we faced them in the Group Stage. They know the way we play and unlike last time, they are well entrenched in their domestic season so they will be sharp and a lot fitter than the last time we played them."
Bunyodkor have also kept faith with largely the same squad which helped the Swallows return to the quarter-finals for the first time since 2009 following back-to-back exits in the Round of 16.
"The Group Stage match against Adelaide in March was our first game of the season. We were right at the start of our new season while Adelaide were reaching the end of theirs which made it difficult for us," said Bunyodkor's Australia midfielder David Carney.
"But now the roles will be reversed as we are in the middle of our season, while Adelaide will be at the beginning of their season in Australia."
And South Korea's Ulsan Hyundai continue their bid to return the continental crown to Korean hands against Saudi Arabia's Al Hilal.
Kim Ho-gon's side, though, must get past 1991 and 2000 Asian Club Championship winners Al Hilal, who thrashed UAE Pro League side Baniyas 7-1 in the Round of 16 at the end of May thanks to four goals from Korean striker Yoo Byung-soo.
"It is great for the K-League. Clubs from the K-league have done a great job in the AFC Champions League for a while and it would be great for Ulsan to add their name to the trophy," said Ulsan captain Kwak Tae-hwi.
"Al Hilal are a great team, but our team is strong as well and if we play our game we can win."
Al Hilal are the only club to have changed coaches since the Round of 16, with former Paris Saint-Germain coach Antoine Kombouare replacing Ivan Hasek.
And Kombouare will be without defender Sultan Al Bishi for the first leg due to suspension.
Elsewhere, 2007 finalists Sepahan will look to build on a promising start to the defence of their Iran Pro League title against Saudi League runners-up Al Ahli, with the first leg taking place on home soil in Isfahan.
Having landed the domestic title for a third consecutive season earlier this year before beating fellow Iran Pro League side Esteghlal in the Round of 16 at the end of May, Zlatko Kranjcar's side have enjoyed a successful start to the new campaign despite undergoing a major summer overhaul.
Seven of the 11 players who started the 2-0 win over Esteghlal in the Round of 16 have departed over the summer including goalkeeper Rahman Ahmadi, defenders Jalal Hosseini and Mohsen Bengar and Brazilian striker Bruno Correa.
Sepahan did make the significant acquisition of Iran striker Mohammad Reza Khalatbari, while also adding Montenegro international striker Radomir Dalovic along with defender Farshid Talebi and goalkeeper Mohammed Bagher Sadeghi.
Like Sepahan's now departed striker Correa, Al Ahli's Brazilian frontman Victor Simoes also found the net on five occasions en route to the quarter-finals, although the Saudi League side have lost the services of Brazilian Marcelo Camacho with coach Karel Jarolim drafting in goalscoring Argentinian midfielder Diego Morales as a replacement.
Al Ahli are a very good team and have good attackers up front and in midfield," said Khalatbari, who helped Zobahan reach the final in 2010.
"Victor Simoes is excellent, as is their Omani striker Amad Al Hosni. It will be a very difficult game, but because we want to get to the final, we will win."
Finally, Al Ittihad continue their bid to join Pohang Steelers as the only sides to have lifted the continental title on three occassions against tournament debutants Guangzhou Evergrande.
Al Ittihad, who won back-to-back AFC Champions League titles in 2004 and 2005, have made an unbeaten start to the new Saudi League season having finished the previous campaign strongly under Spanish coach Raul Caneda.
Egyptian midfielder Hosny Abd Rabo, Bahrain midfielder Adbulla Omar and Congolese striker Fabrice Ondama did depart Prince Abdullah Al Faisal Stadium over the summer, although Caneda was able to bolster his already impressive squad with Brazilian midfielder Diego Souza, former Cameroon international Modeste M'bami and Croatian midfielder Anas Sharbini.
Guangzhou's World Cup winning coach Marcello Lippi, meanwhile, must do without defender Zhang Linpeng and midfielder Zhao Xuri for the first leg due to suspension, while question marks also hang over the availability of Paraguay striker Lucas Barrios.
Barrios has replaced Brazilian striker Cleo in Guangzhou's AFC Champions League squad, although he has endured a turbulent start to his career in China with injury restricting his presence in the team.
Tournament debutants Guangzhou are the first side from China to have reached the quarter-finals since 2006 after Argentinian midfielder Dario Conca scored five goals in seven games, while victory over Al Ittihad will see Lippi's side replicate Shenzhen Jianlibao's run to the 2005 semi-finals.
"All the teams are equal to us. The results of the past are in the past, but we can change the future and we are ready for that challenge," said Guangzhou captain Zheng Zhi.
"Every game will be tough as all of the teams who have qualified for the quarter-finals have good players, but I hope that it will be Guangzhou who will stand out as the best team in the end."
Quarter-Finals (First legs on September 19 and second legs on October 2/3)
Al Ittihad (KSA) v Guangzhou Evergrande (CHN)
Sepahan (IRN) v Al Ahli (KSA)
Adelaide United (AUS) v Bunyodkor (UZB)
Ulsan Hyundai (KOR) v Al Hilal (KSA)
Semi-Finals (First legs on October 24 and second legs on October 31)
Winner Quarter-Final 1 v Winner Quarter-Final 2
Winner Quarter-Final 3 v Winner Quarter-Final 4
Final (November 9 or November 10)
Winner of Semi-Final 2 v Winner of Semi-Final 1