Djokovic, coming off Monday's win at the ATP World Tour Championship, goes against No. 44-ranked Radek Stepanek to kick off the series that will decide the 2013 Davis Cup.
The best-of-five series is to be played on an indoor hard court in Belgrade, Serbia. The Czechs are looking for back-to-back titles, having beaten Spain 3-2 in last year's final. Serbia won its first Davis Cup in 2010 with a team that was anchored by Djokovic.
Djokovic, 5-0 in Davis Cup matches this year, takes a healthy 8-1 career edge over Stepanek, whose lone win in the series came in 2006, into Friday's opener.
The second singles match Friday has seventh-ranked Tomas Berdych going for the Czechs against No. 117th Dusan Lajovic.
Serbia's usual No. 2 would be Janko Tipsarevic but he has a heel injury and isn't expected to play this weekend. The third highest ranked Serb is Viktor Troicki, who is involved in an investigation regarding alleged use of banned substances.
That means Djokovic, despite a very tiring last few months, could be called on to play doubles along with his two singles matches.
As of Thursday, the doubles match Saturday has Czechs Jan Hajek and Lukas Rosol playing Serbs Ilija Bozoljac and Nenad Zimonjic. Czech interim captain Vladimir Safarik, who stepped in after Jaroslav Navratil was hospitalized due to a blood clot, could very well turn to Berdych and Stepanek for doubles while Serbia goes with Zimonjic and Djokovic.
The schedule for Sunday has Djokovic facing Berdych in a Top 10 singles matchup while Lajovic is to meet Stepanek in a potential fifth match of the series.