The second-ranked Serb, who is on a 22-match unbeaten run, has to do what he has done numerous times in the past: win both singles matches to give the small Balkan country a chance in the best-of-five series starting Friday.
However, Serbia's chances were hit Thursday when Janko Tipsarevic was ruled out of the final with a heel injury. Serbia will also miss Viktor Troicki, the star of the 2010 Davis Cup home victory over France. Troicki is out because of a 12-month suspension for skipping a blood test in April.
Thursday's pitted Djokovic against Radek Stepanek and Tipsarevic's replacement, Dusan Lajovic, against Tomas Berdych in Friday's opening singles. The doubles are scheduled for Saturday and reverse singles are Sunday.
"It's a real drawback for our team that we don't have both Janko and Viktor," Djokovic said. "I hope that I can win the first match, the first point is very important as it could release pressure on Lajovic."
The 117th-ranked Lajovic has played only one dead rubber in the Davis Cup, and has no major victories against top players on the ATP Tour.
"I'm very excited that I'll play on Friday," the 23-year-old Lajovic said. "With the support of the crowd, I could maybe surprise Berdych."
Berdych said he has never watched Lajovic play and will try to adjust to his game.
"I will do some scouting before the match," Berdych said. "It is good that this is a best-of-five match and I'll have time to adjust."
Berdych, who has a 13-1 record in Davis Cup doubles with Stepanek, predicted the doubles will decide the winner. Djokovic said that although he has not played many doubles matches in recent years, he would be ready on Saturday if needed.
First, though, he has to focus on the match against Stepanek before deciding whether he would play all three matches in the final.
"Stepanek is a very tricky player," Djokovic said of the Czech veteran. "He likes to rush to the net and change rhythm of the match."
Stepanek said the fact that he's not favoured to win against Djokovic may help his play.
"I'm looking forward to it," Stepanek said. "My advantage is that no one expects me to beat Novak."
Djokovic has won his last four tournaments, including the ATP finals in London, where he beat top-ranked Rafael Nadal 6-3, 6-4 in the final on Monday.
The Czechs are in the final for the third time in five years.