On Centre Court Isner, the No 10 in the world lost 7-6 7-6 to American compatriot Taylor Fritz, who's ranked at 50. Sandgren, who made the quarter-finals of the Australian Open previous year, upset third seed Marco Cecchinato of Italy 6-3, 6-3 and awaits the victor of Argentina's Leonardo Mayer and Italian Matteo Berrettini.
It means that five of the eight seeds have already gone, including Isner, third seed Marco Cecchinato, 2018 Australian Open semifinalist Hyeon Chung and Canadian youngster Denis Shapovalov. "I knew I could", said Fritz. "John's beaten me twice before. We had a lot of close points, and it just feels really good to get through that", he said.
A closely-fought first set saw Norrie edge ahead in the tiebreak, before he went on to convert his first and only break point of the match in the third game of the second set.
The 23-year-old saved all six break points faced to battle past his Portuguese opponent 7-6 (5), 6-4 in an hour and 35 minutes.
Fritz immediately grabbed a mini break and took a 3-0 lead.
Taylor saved a break point already in the second game with a service victor and he converted the third break chance in the fifth game, moving 3-2 up when John sprayed a forehand error.
This time Isner broke back for 4-4 but Fritz took a point against serve again at 6-4, sweeping a backhand victor across court as Isner advanced on the net. "I like to thing one of the strengths of my game is playing under pressure and handling those big moments well".
David tried to play but he chose to retire after he barely managed to move, receiving the special present in the post-match presentation after being one of the most successful players here, winning 32 matches in Auckland after the first appearance in 2003.
New Zealander Rubin Statham was beaten in straight sets by Jan-Lennard Struff of Germany, while New Zealand-born Cameron Norrie of Great Britain won his second round match against Joao Sousa of Portugal in straight sets.
Top seed and two-time champion John Isner is out of the ASB Classic tennis tournament after his first match.
Carreno Busta had an armchair ride into the quarter-finals when Ferrer succumbed to injury just three games into their match.
After receiving medical attention, he returned to the court to play one more point before withdrawing.