An English-trained horse had never won the Melbourne Cup, but Tuesday's result gave England a 1-2-3 finish - Hughie Morrison's Marmelo and Charlie Fellowes' A Prince of Arran joining Appleby.
Meanwhile, second and third place went to Marmelo and A Prince Of Arran.
Favorite Yucatan, prepared by O'Brien, finished 11th, with the Irishman's other entrant Rostropovich fifth in a disappointing race for the master trainer.
The Cliffsofmoher suffered a fractured right shoulder when injured in the Melbourne Cup, unfortunately could not be saved.
"I'm absolutely delighted. This is everybody's dream", said Appleby, who also prepared Epsom Derby victor Masar.
Jockey Kerrin McEvoy celebrated his third win in the two-mile race, drawing level with active jockeys Damien Oliver and Glen Boss.
The victory by Cross Counter notched up 30 Group One wins for Godolphin worldwide this year.
"I did promise (the kids) a swimming pool".
"But Cathy and I have been looking around for a bigger house, and I said to one of the Herald Sun reporters, if I won I'd buy Cathy a new house".
U.S. exempts India from sanctions at Chabahar port in Iran
India has poured $2 billion into Afghanistan since the 2001 US-led overthrow of the Taliban regime, which was also opposed by Iran.
Cross Counter's Melbourne Cup victory is the first by an English horse while it also ended the Godolphin stable and owner Sheikh Mohammed bin Rashid Al Maktoum's long quest to win the "race that stops a nation". It's sinking in now.
"I'm getting wet here but I don't give a stuff because I'm enjoying winning my third Melbourne Cup", McEvoy said.
"This is the one goal, we want to tick this box and win our grand final".
The CliffsofMoher had won $1.7 million dollars for his owners.Today, he broke his shoulder during the 2018 #MelbourneCup & died on track behind the notorious "green screen of death".Animals & #gambling money are a TOXIC mix.Another handsome horse dead. I'm just in a fortunate position to have the horses to make the call on which are the right ones to bring down here.
"What it has done is open the floodgates for Europe winning this just about every single year", he said.
The race was marred when the Aidan-O'Brien-trained The Cliffsofmoher broke down at the winning post the first time around, breaking its leg.
Racing Victoria vets found he was lame in the near foreleg after the race.
That's because of increasing attention being given to The Everest in mid-October.
Wagering data from last year's Melbourne Cup Day showed that, in the immediate lead-up to the main race, a peak of 850 bets a second were being placed through Sportsbet.