Betis qualified for the knock-out rounds of the competition by finishing second in Group I, and will hope to set up a meeting with their city rivals - who face Maribor - by beating last year's quarter-finalists, who sit 16 points off the pace in the Russian Premier League.
But midfielder Juanfran feels progressing will be a challenging task for the side who are bottom of La Liga.
"It's going to be a difficult tie," Juanfran said.
"The cold plays a big part when you travel to a country like Russia so I think it will be a very even tie - I see it at 50-50.
"Things aren't exactly working out for them in their domestic league either.
"(Rubin) have some good players. We will respect them, but we are Betis and we must look to get through."
Meanwhile, two-time winners Sevilla will likely be favourites to qualify from their meeting with Maribor, although coach Unai Emery is not taking the Slovenian side lightly.
"We'll take that draw," Emery commented.
"We always have the utmost respect for every rival we face but considering who we could have got, I think we can be happy.
"We can compete with, and beat, them.
"We are talking about the strongest team in Slovenia. They are top of their league and the fact they have reached this stage says they will not be easy opponents."
