Former Wallabies coach Jones's side raced to a 12-0 lead in Bloemfontein on Saturday before the Springboks got into the game and over-ran them 23-12 to secure the series.
It's the second week in a row England have let a lead slip, with South Africa coming back to win 42-39 in Johannesburg.
The defeat on Saturday was the sixth overall on the trot for England, who also lost to the Barbarians before they left for South Africa.
The tide has seemingly now turned for England and Jones after they rode an unprecedented run of success and looked like a favourite for next year's World Cup in Japan.
"England ... find themselves in a state of freefall, with questions mounting about how can they arrest it," Gavin Mairs wrote in the Daily Telegraph.
"The series defeat, on the back of their fifth-place finish in the Six Nations, has stripped Eddie Jones' side of the status of genuine contenders for next year's World Cup."
Mairs also suggested Jones' job security was now in question, particularly given their fixtures as they finetune their World Cup preparations.
Jones was initially lauded when he took the job after England were knocked out of the 2015 World Cup in the pool phase and led them to 18 successive wins.
Three losses in the Six Nations this year, despite high hopes of becoming the first side to win three successive titles since it expanded in 2000, however, have seen the team slip to fourth in the world.
"One hundred and twenty-six days have now elapsed since England last won a game of test rugby and the long wait goes on," Rob Kitson wrote in The Guardian.
"Whatever magic dust Jones scattered earlier in his tenure has long since disappeared into the ether.
"The postmortem will become even messier if England are flattened again at Newlands, raising fresh doubts about the effectiveness of Jones' training methods and whether or not he can drag things back between now and the World Cup."