Duncan, who has been hampered by a knee injury, will sit out for the eighth time in the Spurs' last 10 games, while Ginobili will miss his fourth consecutive contest due to a hamstring injury.
It's unknown when either player will be able to return.
"It's just about their health," Popovich said. "We need to have those guys healthy and energetic at the end of the year. Things work a whole lot better with them than without them. With [Tim's] knee and Manu's hamstring, I'm not gonna take any chances. If I err, it's going to be on the side of caution."
The Spurs have played just fine without the injured veterans and entered Sunday sporting the NBA's best record (39-12). Prior to Friday's 119-109 loss to the Detroit Pistons, San Antonio had won 11 games in a row.
"I think the guys believe in the system, and they just continue to play," Popovich said.
Since the start of the 2002-03 season, the Spurs are 7-6 in regular-season games that point guard Tony Parker has played without both Duncan and Ginobili, according to the Elias Sports Bureau. Parker has averaged 27 points and 8.3 assists in those 13 games.
The Spurs are 17-1 against the Nets in the last 10 seasons (since 2003-04). According to Elias, that's the best record for any NBA team against a particular opponent during that span.
Nets backup point guard C.J. Watson, who was a game-time decision (sick), is active.
Mike Mazzeo is a regular contributor to ESPNNewYork.com.