The Portugal international is out for eight months after tearing knee ligaments in training last week.
"Danny is a very important player for us but a club like Zenit should not depend on just one player," coach Luciano Spalletti told Russian media.
"Other players must raise their game and help us overcome this problem," added the Italian who last week committed his long-term future to Zenit.
Spalletti has extended his contract with the big-spending club, backed by Russian energy giant Gazprom, until 2015.
Zenit are also without Italy defender Domenico Criscito due to food poisoning and have injury worries over goalkeeper Vyacheslav Malafeyev, midfielder Roman Shirokov and striker Danko Lazovic.
The experienced Malafeyev, who is nursing a calf strain, has kept a clean sheet in the last three Champions League outings including a 0-0 draw at Porto in their final Group G match which secured Zenit a place in the knockout round for the first time.
If Malafeyev does not recover in time, Spalletti is likely to bring in Belarus international Yuri Zhevnov who has yet to play in the competition.
With temperatures dipping below -15 Celcius in St Petersburg over the past week, officials said they would make a decision on the match shortly before kick-off.
"Should we play in such freezing cold? I don't think so. The ball feels like a rock, you could easily break a leg," said Shirokov.
If the game goes ahead Zenit must hope their notoriously hostile fans are on their best behaviour following crowd trouble at their last Champions League home game against APOEL Nicosia in November.
European football's ruling body UEFA fined the Russians 30,000 euros ($39,600) and warned of a heavier penalty if it happened again.
Benfica are brimming with confidence. They finished top of Group C, helping to knock out Manchester United, and are undefeated at the top of their domestic league, five points above Porto.
Silky playmaker Pablo Aimar has been the main creative influence and he extended his contract last week until June 2013.
Benfica coach Jorge Jesus relies on a stable defence and is spoilt for choice in midfield and up front with a host of options including Argentine Nicolas Gaitan, Brazil's Bruno Cesar and Spaniard Nolito.
Argentine Javier Saviola is also among the contenders to start in attack alongside Paraguay striker Oscar Cardozo.
Zenit St Petersburg: 16-Vyacheslav Malafeyev or 30-Yuri Zhevnov; 2-Alexander Anyukov, 3-Bruno Alves, 6-Nicolas Lombaerts, 14-Tomas Hubocan; 15-Roman Shirokov, 20-Viktor Faizulin, 18-Konstantin Zyryanov, 27-Igor Denisov; 8-Danko Lazovic or 34-Vladimir Bystrov, 11-Alexander Kerzhakov.
Benfica: 1-Artur; 14-Maxi Pereira, 4-Luisao, 24-Ezequiel Garay, 3-Emerson; 21-Nemanja Matic, 28-Axel Witsel, 20-Nicolas Gaitan; 10-Pablo Aimar, 19-Rodrigo, 7-Oscar Cardozo.
Get the best features, fun and footballing frolics straight to your inbox every week.
Thank you for signing up to Four Four Two. You will receive a verification email shortly.
There was a problem. Please refresh the page and try again.