Liverpool and Manchester United have warned fans any offensive behaviour during Monday's meeting will result in ejection from Anfield.
The fixture between England's two most successful clubs and arch-rivals has been littered with unsavoury incidents between the two sets of supporters off the pitch.
Last season Liverpool were fined £30,000 - half of which was suspended - by UEFA for illicit chanting, setting off fireworks, throwing objects and crowd disturbances following their Europa League last-16 tie at Old Trafford.
United received a similar punishment for crowd disturbances and the throwing of objects at the same match, prior to which police had to remove a 'Murderers' banner (in reference to the Heysel and Hillsborough disasters) which was hung on a bridge above a motorway used by Liverpool fans on their way to Old Trafford.
"Both clubs, their supporters and football fans around the world are looking forward to this historic and passionate match between two of the sport's biggest and oldest rivals," said a joint statement from the clubs, who say they continue to work together and respect the great rivalry between the two but will not condone any offensive or discriminatory behaviour.
"There is great rivalry between our fans and we ask all supporters to be respectful and help eradicate all forms of offensive and discriminatory behaviour from the game.
"If any supporters are found to be engaged in any form of offensive or discriminatory behaviour by stewards or via CCTV then they will be immediately removed from the stadium, risk arrest, prosecution and be reported in accordance with the club's ground regulations.
"This is an unrivalled fixture in the Premier League calendar and we thank all fans for their continued support in this important area of the game."
Monday's match - only the fifth evening kick-off in the last 35 years - could be watched by an estimated 700 million people in over 200 countries, according to broadcasters Sky Sports, and the clubs involved are doing all they can to ensure it passes off without incident.
Previous encounters have been marred by chants from both sets of fans about Hillsborough, where 96 Liverpool fans died, and the Munich air disaster, which claimed the lives of 23 people in 1958 including eight United players and three staff.
Kick it Out, football's equality and inclusion organisation, welcomed the proactive move.
"Both Liverpool and Manchester United should be commended for this proactive approach ahead of this important fixture," said a spokesman.
"We always encourage supporters to report any form of discrimination they may see or hear.
"Our reporting app, which is available to download from the App Store and Google Play, allows users the option to attach photos and videos."