Djokovic won his 15th consecutive match at the All-England Club, defeating British wild card Jack Draper 4-6, 6-1, 6-2, 6-2 while Anderson knocked off Marcelo Tomas Barrios Vera 6-7 (4), 6-4, 6-4, 7-6 (4), firing 40 aces in the victory.
This is the 12th career meeting between the Serb and South African with Djokovic holding a 9-2 edge. Their last meeting was at last year's ATP Cup with the world number one prevailing in two tiebreakers.
Their most memorable meeting was in the 2018 final at this tournament with Djokovic coming out on top 6-2, 6-2, 7-6 (3) to capture his 13th major title.
The winner of this match will face the winner of the match between Andreas Seppi and Denis Kudla in the third round.
The key for Anderson will be how he serves. It's his best shot and one of the best in the game. Varying the direction of it to keep Djokovic off-balance will be key if the South African is to have success.
Another important factor will be the Anderson forehand as he will want to dictate the rallies from that side and play shorter points as longer rallies will heavily favor the world number one.
Djokovic is the best mover and returner on tour and he will want to extend the points at every opportunity. His backhand will also do most of the damage off of the ground. If Anderson can stay neutral on those exchanges, he has a chance.
Djokovic is mainly playing against history at this point. He'll be favored in every match he plays in 2021 as he chases history. It's that narrative that actually gives Anderson a small chance to pull off the upset.
He has the weapons to trouble Djokovic and if he can get out in front early, the pressure of trying to win the calendar-year Grand Slam may come into play.
Still, Djokovic is obviously the heavy favorite to win this match as he will likely grind Anderson down, sneak out a break or two per set and keep the rallies long enough to force the South African into errors. Don't expect a straightforward match, but the world number one will move on.
Prediction: Novak Djokovic in four sets