Supporters of Sofia rivals CSKA and Levski, as well as fans of Botev Plovdiv and Lokomotiv, will pour into the Vasil Levski national stadium hoping that Ludogorets, 1-0 up from the first leg of the last-32 tie, can extend their fairytale campaign.
Bulgarian football is suffering from crowd violence, refereeing scandals and match-fixing allegations, and many fans have given up on the club game.
"I'm a CSKA fan and I watch most of their matches on TV, but I don't go the stadium more than once or twice a year," Hristo Kostov told Reuters.
"I love football but there's too much violence in the stands while Ludogorets matches are something different. It's so comfortable and safe to be there ... I'm looking forward to the Lazio match and I hope they knock the Italians out."
The Eagles reached this season's Europa League knockout stages after topping Group B unbeaten, ahead of PSV Eindhoven, Chernomorets Odessa and Dinamo Zagreb.
Ludogorets are based in a town with a population of less than 35,000 people and play their home matches at their 8,000-capacity Ludogorets Arena.
But they have to move to the 43,000-seater Vasil Levski stadium in the centre of Sofia for their European games because it's the only suitable arena in the country.
"I travelled all the way from Burgas (some 390 km from Sofia) and I even quarrelled with my wife but I wanted to be at the stadium so much," said Daniel Angelov.
"Ludogorets are the best team in Bulgaria at the moment and I'm sure they'll beat Lazio once again."
Local media reported several hundred fans from neighbouring countries have also made the trip to watch the game.
"More than 30,000 people will be at the stadium and it's great," said Ludogorets winger Mihail Alexandrov. "I'm so pleased to see that all Bulgarian fans are united."
Bulgarian clubs have rarely tasted success in Europe since the fall of communism in 1989.
The country is limited to one place in the qualifying stages of the Champions League and Levski remain the country's only representative in the group phase, in 2006.