Wearing the red jersey as leader in the points classification, Cavendish powered past his rivals on the closing straight of the 254km stage from Busseto to edge out Italian Giacomo Nizzolo and Slovenian Luka Mezgec in a pulsating finish after more than six hours in the saddle.
Race leader Vincenzo Nibali (Astana) finished safely in the peloton to retain his 41-second lead over Cadel Evans (BMC) in the general classification.
With Britain's Bradley Wiggins (Team Sky) pulling out of the race because of a chest infection, Cavendish gave British fans something to cheer with his fourth win of the race - and the 101st of his illustrious career.
The Omega Pharma-Quick Step sprinter showed huge character and strength to stay on the front of the main pack over a succession of hills in the Barolo wine region towards the end of the long stage in northern Italy.
Marshalled expertly by his team-mates through the uphill obstacles, the 27-year-old then had to finish off the job on his own after entering the final kilometre of the stage isolated and off the front.
With the Cannonale team of Elia Viviani leading out the final sprint from afar, Cavendish came from eight riders back to roar past his rivals and take yet another brilliant win.
RadioShack-Leopard youngster Nizzoli pushed Cavendish all the way for second place, while Argos Shimano's Mezgec showed once again that he is more than a mere lead-out man for the now-departed John Degenkolb with a strong surge for third.
In the absence of Australia's Matt Goss - who had been dropped on the Cat.3 Tre Cumi climb 40km from the finish - Orica-GreenEdge's Brett Lancaster burst past Viviani to take fourth.
Cavendish said his fourth win of the 96th edition of La Corsa Rosa was "a bit of a bonus" but admitted he was not keen on contesting for the spoils ahead of what proved to be a tough slog in the sun.
"I am so tired," he said. "I don't know how I am going to recover from this ahead of the mountains.
"I had to go from 350 metres after such a hard day. I'm on my knees now. I didn't even want to go for the sprint today but Cannondale were going for it and the guys worked so hard for me."
The first challenge for OPQS was to reel in a break of seven riders which had built up a huge lead of 13 minutes on a rare day largely unaffected by the rainfall that has blighted this year's Giro.
Germany's Danilo Hondo (RadioShack), Spain's Pablo Lastras (Movistar), Swede Tobias Ludvigsson (Argos Shimano), Denmark's Lars Bak (Lotto Belisol), Italians Nicola Boem (Bardiani Valvole) and Giairo Ermeti (Androni Giocattoli) and Brazilian Rafael Andriato (Vini Fantini) forged a gap 30km after the start in Busseto, the birthplace of the composer Giuseppe Verdi.
The break was a blend of youth and experience, with old-hands Hondo, Lastras and Bak - all former stage winners on the Giro - combining well with first-year pros Boem and Ludvigsson, track specialist Ermeti and the race's only rider from Brazil in Andriato.
At just 22 years of age, Ludvigsson was just 10 years old when Lastras and Hondo last won their stages on the Giro back in 2001.
With 165km remaining, the gap hit its peak of 13 minutes. But just after the feeding zone, Cannondale came to the front of the peloton and combined with OPQS in reducing the deficit.
At times the pace was so high in the chasing pack that echelons formed splitting the peloton in two.
The advantage came tumbling down: by the time Andriato had won his second successive intermediate sprint in Alba - renowned for its truffles and hazelnuts, and the home of Nutella chocolate spread - the gap was just 1min 14secs with 50km remaining.
Concerned that perhaps the gap was coming down too quickly, the peloton eased up to allow the seven leaders to stretch out their advantage to three minutes.
On the only categorised climb of the day, the Cat.3 Tre Cuni, Italian youngster Boem attacked his fellow escapees and was joined by Lastras and Bak with 45km remaining.
The trio passed over the summit with just 25 seconds to play with after the peloton was led over by blue jersey Stefano Pirazzi (Bardiani Valvole), who took the final point to consolidate his lead at the top of the KOM standings.
A counter attack formed around former pink jersey Luca Paolini (Katusha) but OPQS upped the tempo to reel in the riders.
When Boem cracked with 16km to go, Lastras then dropped Bak and went for a long solo attempt. But a counter group had formed off the front of the peloton as the race zipped over undulating roads flanked by the Barolo vineyards.
The chasing group caught Bak and then Lastras to form a nine-strong leading group riding just 15 seconds ahead of the peloton.
Italian Giampaolo Caruso (Katusha) attacked with 5km to go but was reeled in by the returning peloton inside the final 2km.
Having worked so hard in chasing down the numerous breaks, Cavendish's team-mates were unable to set up their man in the final sprint - and it was Cannondale who had two riders dragging Viviani towards the line.
But Cavendish used his supreme kick to leave his rivals for dead and underline once again just why he's the world's fastest man on two wheels.
Victory for Cavendish sees him open up a large gap at the top of the red jersey standings, where he leads Australian veteran Evans by 108 points to 73.
Focus now turns to the fight for GC with two back-to-back stages in the Alps. Nibali takes a 41 second lead over Evans into the mountains with Colombia's Rigoberto Uran - the stage 10 winner and now top dog at Team Sky following Wiggins's withdrawal - 2:04 down in third place.
Saturday's 168km Stage 14 includes the tough Cat.2 climb to Sestriere ahead of a final summit finish in Bardonecchia while Sunday's queen stage concludes with an ascent up the revered and feared Galibier climb in France.
- Sports & Recreation
- Cadel Evans
- Bradley Wiggins
- Pablo Lastras
- Elia Viviani