Arsenal will face Liverpool twice, as well as Manchester United and Bayern Munich, in the space of 11 days during February, while March sees them take on Bayern, Tottenham, Chelsea, Manchester City and Everton.
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"It's an interesting draw [against Liverpool] and a difficult one. We have a little advantage by playing at home," he told reporters.
"There will be plenty of big games, which means whole squad needs to be highly focused. It is a massive challenge, but I am confident we can do that. It's very important I get it right on the rotation front."
Looking ahead to Arsenal's clash with Southampton, Aaron Ramsey, Mikel Arteta and Thomas Vermaelen could all return, while Alex Oxlade-Chamberlain may be ready for his first start since the opening day of the season.
The league leaders travel to St Mary's looking to record an eighth consecutive victory in all competitions, but Wenger knows doing so will be a tough ask against Mauricio Pochettino's side.
"Everybody goes to Southampton now knowing they are in for a very difficult game," he added. "[Pochettino] has done a very good job because nobody knew him when he came here.
"Southampton have done a remarkable job with their academy. The quality of their work is amazing.
"We have a doubt about Wilshere but Ramsey, Arteta and Vermaelen are back in the squad. [Oxlade-Chamberlain] is not fully fit but he is getting closer. I haven't decided whether he will start tomorrow."