Passengers were said to have joined in to help staff restrain the brawlers and an air stewardess was slapped in the fracas.
It was filmed by Tommy Engerer, who told The Sun's Nick Parker the terrifying and lengthy incident led to him thinking the men would try and open the doors to bring the plane down.
The fight was sparked by a pensioner who was hit on the head after moving seats, Mr Engerer said, which prompted two Belgian men to intervene.
The men involved are understood to have been arrested by Italian police.
Ryanair told MailOnline: 'This flight from Brussels to Malta on November 3 diverted to Pisa after a number of passengers became disruptive inflight.
"The aircraft landed normally and four passengers were removed and detained by police upon arrival, before the aircraft continued to Malta.
"We will not tolerate unruly or disruptive behaviour at any time and the safety and comfort of our customers, crew and aircraft is our number one priority.