Cerundolo capped a dream week in Buenos Aires, where the 19-year-old qualifier upstaged fifth seed Albert Ramos-Vinolas 6-0 2-6 6-2 in Sunday's final.
With the memorable triumph, Cerundolo became the only Argentinian in the Open Era to win a title in their tour-level debut.
Cerundolo also became the youngest ATP Tour champion from Argentina since 2001 and the first player to win on their bow since 2004.
The world number 335 – who had only played 14 matches on the Challenger Tour, owning a 7-7 record – is the fifth-lowest ranked winner in ATP Tour history.
A day after first and third seeds Fabio Fognini and Karen Khachanov were knocked out, second seed Shapovalov was beaten 7-5 6-4.
Humbert, who broke serve in the final game of each set, described the win as "one of the biggest of my career" as he set up a semi-final against John Isner.
The American was taken to two tie-breaks by Kyle Edmund but prevailed 7-6 (7-5) 7-6 (7-5), his 25 aces getting him over the line as he seeks a third title in Auckland.
Benoit Paire reached his first semi-final at the event, coming from a set down to beat John Millman 3-6 6-1 6-4.
The fifth seed will face Hubert Hurkacz, who spurned six second-set match points in a mammoth tie-break before eventually seeing off Feliciano Lopez 6-4 6-7 (11-13) 6-4.
At the Adelaide International, home favourite Alex Bolt was soundly beaten by Felix Auger-Aliassime, the Canadian needing just 55 minutes to win 6-3 6-0.
He will meet Andrey Rublev in the last four after the Russian battled past Dan Evans 6-4 3-6 6-3 in just over two hours.
Spanish hopes were extinguished in the quarter-finals, where Tommy Paul surprised Albert Ramos-Vinolas to win 6-3 6-4 and Lloyd Harris beat fourth seed Pablo Carreno Busta 6-3 6-3.
