Juan Martin Del Potro, Andy Murray, Kevin Anderson, Marcos Baghdatis, Stanislas Wawrinka, Mikhail Youzhny and Andreas Seppi joined Hewitt and Karlovic as the notable winners on a rain-effected third day's action at Flushing Meadows.
Meanwhile, Blake was joined as being bundled out by Radek Stepanek, Nicolas Mahut, Xavier Malisse and Jurgen Melzer.
Hewitt returned for his 13th US Open having been a past winner in 2001 and the 32-year-old Australian had a tough battle up against 28-year-old American, but ended up prevailing in four tight sets 6-3, 4-6, 6-3, 6-4.
Hewitt was handed the victory when Baker served his 10th double-fault of the night and that gave the Australian former world No. 1 a remarkable 10th break of serve for the match.
Hewitt created 19 break point opportunities against Baker and converted 10 of them while the American had 12 and converted seven himself.
Neither player served well with Hewitt finishing with eight aces and seven double faults while just 46 per cent of his first serves landed in, and he won just 46 per cent of his second serves. Baker landed just 49 per cent of his first serves and won only 45 per cent of his second serves.
However, Hewitt had just 27 unforced errors for the match with 28 winners while Baker had a massive 72 unforced errors with 55 outright winners.
The second round looks daunting for Hewitt, though, with Argentine world No. 6 Del Potro awaiting after he beat Spaniard Guillermo Garcia-Lopez 6-3, 6-7 (5), 6-4, 7-6 (7).
Del Potro and Hewitt have become good friends in recent years on Tour and the Argentine is known to have had the Australian as his hero growing up, but it looms as a fascinating second round clash.
The other Australian man in action in Round 1 matches on the third day saw James Duckworth lose in four sets to American Tim Smyczek 3-6, 6-2, 6-4, 6-1.
With the victory, Smyczek moves into the second round where he will play Russian Alex Bogomolov Jr who needed five sets to overcome Frenchman Benoit Paire 7-5, 2-6, 6-4, 5-7, 7-6 (5).
Defending champion and world No. 3 Murray was the last men's match to get underway for the night on Arthur Ashe Stadium and he cruised to a 6-2, 6-4, 6-3 win over French veteran Michael Llodra, but he did have to fight back from losing the first three games of the second set.
Murray will now play Argentina's Leonardo Mayer who beat Romania's Victor Hanescu 7-6 (4), 6-4, 3-6, 7-6 (4).
The match of the day, though, was without doubt between retiring American 33-year-old Blake and giant Croatian Karlovic on Louis Armstrong Stadium.
Blake announced coming into his 13th US Open that he would be retiring when he lost in the tournament but he got off to a bright start against the huge-serving Croatian winning the opening two sets.
However, the big serving and hitting of Karlovic wore down the veteran American and he eventually won when he took out the fifth-set tie-break, 6-7 (2), 3-6, 6-4, 7-6 (2), 7-6 (2).
It brings to an end a glittering career from Blake who reached a career-high ranking of No. 4 in 2006, won 10 career titles, was part of the USA's winning Davis Cup team of 2007 while reaching the quarter finals of both the Australian Open and US Open.
He also won Perth's Hopman Cup year-opening tournament twice, with Serena Williams in 2003 and Lindsay Davenport in 2004, while winning almost $8-million in prize money as one of the most popular and respected players in the game over his career that began in 1999.
Karlovic advances to the second round, though, where he will face Swiss world No. 9 Wawrinka who won a tight three-setter against Czech veteran Stepanek, 7-6 (2), 6-3, 6-2.
Another big man, South Africa's Anderson is also through to the second round after the 17th-seed beat German Daniel Brands 7-5, 4-6, 6-2, 6-3.
Anderson next plays popular Cyprus veteran Baghdatis who won his first round clash on Day 3 with Japan's Go Soeda 6-4, 6-3, 6-1.
American Rajeev Ram had a first round to remember at his home Grand Slam when he thumped 16th-seeded Italian Fabio Fognini 6-1, 6-2, 6-2 to set up a second round match-up with Spain's Marcel Granollers who beat Estonia's Jurgen Zopp 6-1, 3-6, 1-6, 6-3, 6-4.
India's Somdev Devvarman prevailed in another five-set battle against Slovak Lukas Lacko 4-6, 6-1, 6-2, 4-6, 6-4 to now set up a second round clash with Italian 20th-seed Seppi beating Belgian veteran Malisse 6-3, 3-6, 7-5, 7-5.
Perhaps one of the toughest first round match-ups to tip coming into the US Open was between Russian Youzhny and Frenchman Mahut, and it played out that way in three tight-sets with the 21st-seeded Russian winning 6-4, 6-4, 7-6 (4).
Youzhny now faces Alexandr Dolgopolov from the Ukraine in the second round he beat Belgian David Goffin 6-2, 6-4, 6-4.
German Peter Gojowczyk beat Dutchman Igor Sijsling 7-6 (7), 2-6, 6-4, 6-1 and Russian Evgeny Donskoy beat Austrian No. 29 seed Melzer 7-5, 6-3, 7-6 (3) in other Day 3 action.
Day 4 men's action is highlighted on Arthur Ashe Stadium with the second round getting underway with Roger Federer taking on Carlos Berlocq and Rafael Nadal playing Rogerio Dutra Silva.
On Louis Armstrong Stadium, David Ferrer is facing Roberto Bautista Agut and John Isner taking on Gael Monfils in likely the match of the day.
Other men's match-ups of note include Nikolay Davydenko taking on Ivan Dodig, Tommy Robredo playing Frank Dancevic and Sam Querrey battling Adrian Mannarino.