On a cloudy day in Centurion, the hosts found themselves 57-3 as West Indies' bowlers made early inroads, however they were then made to toil as the experienced pair settled in.
Together they put on an unbeaten 283 for the fourth wicket, a new record, and both men remained unbeaten at the close, with 150 apiece firmly in their sights on day two.
De Villiers is closer to the milestone with only nine needed on Thursday after finishing the day 141 not out, an innings that saw him strike 15 fours and two sixes to bring up a 20th Test century.
At the other end Amla (133 not out) went past three figures for the 23rd time with a supreme innings littered with elegant strokes on both sides of the wicket.
Kemar Roach (2-52) stood out with the ball, but the pace bowler's day ended early as he limped off the field before finishing his 16th over.
After an early rain delay, the West Indies won the toss and elected to bowl in what appeared to be favourable conditions and, although runs flowed early, they took three wickets in two overs to worry South Africa.
Roach removed Alviro Petersen (27) in the 14th over with a beautiful delivery that straightened, taking the outside edge on its way to Devon Smith at first slip.
Dean Elgar (28) and Faf du Plessis both followed within 15 balls, the latter for a duck, without adding to the score leaving the hosts 57-3.
With Amla and De Villiers at the crease they pulled away from trouble, although both men had some luck when building their impressive partnership.
Roach was the man to cause all the problems as he moved the ball around off the seam, first having an lbw appeal turned down against De Villiers before watching in amazement as a delivery clipped Amla's off stump but failed to remove the bails.
Amla survived one more time as Roach jagged a delivery back into him, but again the 26-year-old's appeals for lbw were dismissed.
Both men quickly put those chances behind them and rarely offered another chance as they plundered runs all over the ground, with extra cover proving particularly popular.
De Villiers went to three figures first with a simple nudge to mid-off, and his partner followed him four overs later with a cut to the off-side boundary.
West Indies continued to push for a late breakthrough but both batsmen were well set and rarely troubled, and will have their sights sets on further milestones on day two.