The 6ft 9in Isner blasted 17 aces against the 6ft 8in South African to prevail in 79 minutes and will play Frenchman Edouard Roger-Vasselin for a place in the final.
Roger-Vasselin was too good for Lithuania's Ricardas Berankis, advancing with a fuss-free 6-4 6-3 victory.
Second-seeded German Tommy Haas had more trouble getting past Croatian Ivan Dodig but prevailed 7-6 2-6 6-1.
Haas, the 2006 champion, will meet 2010 winner Ernests Gulbis of Latvia in the other semi-final.
Both 34-year-old Haas and Dodig struggled on serve throughout their match but the German veteran captured an early break to steal a march in the third and rode the momentum to victory.
"Right now I have to be very thankful my body is holding up great," said former world number two Haas, the oldest player in the men's top 50.
"When the third set started I was feeling, 'OK, here we go, let's just try to get a good start' - and I had a good start breaking him right away."
The 19th-ranked Haas has enjoyed a late career renaissance following two injury-blighted years with hip and elbow problems and was named ATP Comeback of the Year in 2012 after climbing 184 spots to break into the top 25.
He faces an opponent 10 years his junior in Gulbis.
"I'm not so worried about my age," said Haas, who made the final at the San Jose Open last month.
"I'll worry about it when my birthday comes along and I'll recognise the fact I'm going to turn 35 and I'll celebrate it.
"But when you're on the court competing against somebody who's 20 or 25 it doesn't matter. You're out there trying to win."
Gulbis came back from 0-4 in the deciding set to defeat Sam Querrey on Thursday, but was much more clinical in his 6-1 6-4 defeat of Spaniard Daniel Munoz.
Delray Beach International results
1-John Isner (U.S.) beat 6-Kevin Anderson (South Africa) 6-2 7-6(1)
Edouard Roger-Vasselin (France) beat Ricardas Berankis (Lithuania) 6-4 6-3
2-Tommy Haas (Germany) beat Ivan Dodig (Croatia) 7-6(6) 2-6 6-1
Ernests Gulbis (Latvia) beat Daniel Munoz (Spain) 6-1 6-4
- Sports & Recreation
- Ernests Gulbis
- Ivan Dodig