The first half was dull, with Joe Gomez's injury the only major talking point at the half-time interval given neither side mustered a shot on target.
However, Ryan Hardie would give the Championship hosts the lead from the penalty spot less than 10 minutes into the second half after Harvey Elliott blocked a flick on in the box with his hand.
Hardie could have made it 2-0 but hit the post at the hour mark after a mix up by Liverpool's defenders when defending a set piece, but despite facing significant pressure late on, his miss mattered little as his earlier goal was enough to advance to the next round.
Liverpool's dreams of winning a quadruple are over, while Plymouth boss Miron Muslic earned just his second win in his six matches in charge and saw his side advance to the fifth round of the FA Cup.
SPORTS MOLE'S VERDICT
Liverpool were arguably seen as the favourites to win the FA Cup given Arsenal and Chelsea's exit from the competition, and they will feel that their elimination at the hands of Plymouth, who are last in the Championship, has seen them miss out on a good chance at silverware.
However, Reds boss Arne Slot left out numerous starters from his travelling squad, and he has clearly prioritised resting key players for their Premier League match against Everton on Wednesday.
Plymouth manager Muslic inherited a difficult situation from previous head coach Wayne Rooney in January, but he has now won two consecutive games, as many as his side had won in their prior 17.
The victors could use the victory as a platform from which to climb up the Championship table and stave off relegation, and with the gap to safety standing at just four points, survival is by no means an impossibility.
PLYMOUTH ARGYLE VS. LIVERPOOL HIGHLIGHTS
11th min: Joe Gomez (Liverpool) injury
After just 11 minutes Liverpool captain Joe Gomez goes down with what appears to be a muscle injury, and he hobbles off the pitch for Isaac Mabaya, who will slot in at right-back while Wataru Endo will drop to centre-back.
Ryan Hardie goal vs. Liverpool (53rd min, Plymouth Argyle 1-0 Liverpool)
Harvey Elliott bizarrely handles the ball in the area after Darko Gyabi flicked the ball in the penalty area, and Ryan Hardie coolly converts the spot kick into the bottom-left corner, sending Caoimhin Kelleher the wrong way
The Championship side take the lead!
90 + 9th min: Conor Hazard (Plymouth Argyle) save
Kostas Tsimikas sends in a free kick from the left flank, and the Reds manage to head the ball across goal to Darwin Nunez, and the strike stretches to head home but goalkeeper Conor Hazard leaps to tip his shot behind for a corner.
What a save!
MAN OF THE MATCH - NIKOLA KATIC
Nikola Katic was at the heart of everything for Plymouth on Sunday, making 17 clearances and 22 defensive actions against Liverpool.
The centre-back had to endure an onslaught in the latter stages of the game, but he excellently tracked striker Darwin Nunez into the box, and made sure to win his aerial battles when Harvey Elliott played crosses into the penalty area.
PLYMOUTH ARGYLE VS. LIVERPOOL MATCH STATS
Possession: Plymouth Argyle 25%-75% Liverpool
Shots: Plymouth Argyle 10-14 Liverpool
Shots on target: Plymouth Argyle 2-4 Liverpool
Corners: Plymouth Argyle 4-7 Liverpool
Fouls: Plymouth Argyle 9-7 Liverpool
BEST STATS
WHAT NEXT?
Plymouth return to Championship action on Wednesday against Millwall, before playing Blackburn Rovers on February 15.
As for Liverpool, they face a difficult Premier League test against Everton on Wednesday, and they then take on Wolverhampton Wanderers on February 16.
Written by
Lewis Nolan