Philander was taken to hospital on the second evening with a stomach virus, with the Proteas going on to lose by 239 runs despite the all-rounder's return on the third morning.
"Vern's such a good player you'd almost take him at 50%," Du Plessis said. "The plan was to win the toss, bat and give him a day to get better, so not to have him for two days was a big loss."
As it transpired, England won the toss and batted first with Philander taking regular trips from the field as the hosts eventually made what proved to a decisive first innings score of 353 all out.
Philander, 32, who has 141 Test wickets from 41 matches, bowled only 32 overs in the match and was wicketless in the second innings as England took a 2-1 series lead.
"It's obvious to say someone like Vernon Philander missing out on that first innings was costly," said Du Plessis.
"They got 100 runs too many in that innings, but you have to say England batted well."
England bowled out the tourists for 175 in their first innings, taking seven wickets inside 18 overs under the floodlights in drizzly, overcast conditions on Friday afternoon.
Opener Dean Elgar made a gritty 136 in the second innings but the Proteas were eventually bowled out for 252 before tea on the final afternoon.
"The end of day two was probably the most difficult conditions you'll see in Test cricket," said Du Plessis, who made one and a first-ball duck - dismissed padding up and offering no shot on both occasions.
"It's been a strange series - mistakes were made in this Test, we don't have to scratch our heads to know what to do about it.
"Dean's knock was amazing, and something our batters can look towards to make sure they go out and fight.
"We lost most of our main batters yesterday but the guys fought really well today so there are positives to take. Dean showed us what was needed."
The final match in the series begins at Old Trafford on Friday.
South Africa captain Faf du Plessis conceded his side's gamble on Vernon Philander's fitness backfired during their third Test defeat at The Oval.