Six Championship games on 26 December and 15 more across the EFL have been called off because of Covid-19 cases.
Cardiff v Coventry, Millwall v Swansea, Fulham v Birmingham, Stoke v Barnsley, Peterborough v Reading and Preston v Sheffield United are postponed.
Seven games in League One and eight in League Two have also been called off.
The English Football League has confirmed that league, Carabao Cup and Papa John's Trophy games can continue "where safe to do so".
Only four of the scheduled 10 Championship matches on Boxing Day remain on, while five games in the National League have also been postponed.
Several EFL fixtures on 29 and 30 December have also been postponed.
League Two leaders Forest Green head the list of six games called off in the fourth tier on 26 December with their trip to Newport off. Their home game against Exeter on 29 December is also postponed.
Bristol Rovers v Sutton United, Northampton Town v Walsall, Bradford City v Harrogate, Stevenage v Crawley Town, Exeter City v Swindon Town, Leyton Orient v Colchester and Port Vale v Salford are all postponed on Boxing Day.
Bradford's match against Walsall on 29 December is one of two in the division off on that day.
The League One match between Bolton and Morecambe became the first Boxing Day fixture in the division to be called off on Tuesday - with the Trotters since suspending training until 27 December as 14 players, and manager Ian Evatt, have tested positive for coronavirus - while Portsmouth against Oxford United is also off.
Sheffield Wednesday against Burton Albion, Wycombe versus Cambridge United, Gillingham against Ipswich, AFC Wimbledon against Charlton Athletic and Crewe versus Wigan are all postponed.
Cambridge's home game against Doncaster on 30 December is also off.
Following the introduction at clubs of daily lateral flow tests for all first-team players and staff, more fixtures are likely to be postponed as national figures rise following the effect of the Omicron variant.
"Throughout the pandemic, our two priorities have been ensuring the welfare of those involved in EFL competitions and ensuring the fixture schedule can continue where it is safe to do so," said EFL chief executive Trevor Birch.
"We will continue to work with clubs, authorities and other agencies to monitor the Covid-19 case rate and be prepared to respond accordingly. Yet, for now, the view remains that we can continue to deliver games safely where clubs have sufficient healthy personnel in place, on and off the pitch.
"With club mitigation measures, the mass adoption of booster jabs and Covid certification now required for larger crowds, we are sure many fans will continue to feel confident in attending matches over the Christmas period and we look forward to welcoming them."
Barnsley v Stoke City
Cardiff City v Coventry City
Fulham v Birmingham City
Millwall v Swansea City
Peterborough United v Reading
Preston North End v Sheffield United
AFC Wimbledon v Charlton Athletic
Bolton Wanderers v Morecambe
Crewe Alexandra v Wigan Athletic
Gillingham v Ipswich Town
Portsmouth v Oxford United
Sheffield Wednesday v Burton Albion
Wycombe Wanderers v Cambridge United
Bradford City v Harrogate Town
Bristol Rovers v Sutton United
Exeter City v Swindon Town
Leyton Orient v Colchester
Newport County v Forest Green Rovers
Northampton Town v Walsall
Port Vale v Salford City
Stevenage v Crawley Town
Barnet v Boreham Wood
FC Halifax Town v Grimsby Town
Wealdstone v Maidenhead United
Weymouth v Eastleigh
Wrexham v Solihull Moors
Boreham Wood v Wealdstone
Grimsby Town v King's Lynn Town
Yeovil Town v Weymouth
Bradford v Walsall
Forest Green Rovers v Exeter City
Cambridge United v Doncaster Rovers