After seeing a deflected 20-yard shot beat Fabian Bredlow in the first half, Reus reached the milestone after the restart with a cool finish into the bottom-right corner at the end of a neat exchange with Jacob Bruun Larsen.
It was Bruun Larsen who got the rout started in the ninth minute with a fine lob after excellent work from Christian Pulisic.
Reus added an assist to his first goal by teeing up Achraf Hakimi to make it 3-0.
Following the Dortmund skipper's landmark strike, Manuel Akanji got in on the act by dispossessing Tim Leibold in the box and firing home in the 74th minute.
Substitutes Jadon Sancho and Julian Weigl notched inside the final five minutes to complete a commanding win for Lucien Favre's side.
"Scoring the 100th goal means a lot to me," he told assembled media after the game.
"It's a great honour. It took long enough, and I hope that those won't be the last goals I score for the club. I hope it continues like that."
"I wouldn't necessarily say that it was easy, but you can say that Nurnberg were very passive today," he said.
"They set up with a back five and were not very aggressive. Because of that, we could cleanly build from the back and quickly created scoring chances.
"Nevertheless, it was important that we scored goals early. Christian [Pulisic] and Jacob [Bruun Larsen] created an outstanding goal and we never let up after that, creating loads more chances."