Speaking in what may be his last Commons appearance in his job, Mr Grayling was asked by Bradford MP Judith Cummins about the disruption which will be caused in late August.
Three days of disruption from August 24-25 will hit spectators attending the Ashes Test at Headingley; York’s Ebor Festival and rugby league’s Challenge Cup final. Leeds Festival revellers will also be affected.
Labour MP Ms Cummins said: "The decision by Network Rail to shut the East Coast Main Line on the Bank Holiday weekend is as baffling as it is nonsensical.
"Tens of thousands of people will be travelling to the North four our great sporting and cultural events while Rugby League fans are heading to Wembley for the Challenge Cup final. The economic impact on the North is likely to be significant.
"Can the Minister tell us when his department was first told about this decision and whether he will step in now to reverse it and prevent this misery for passengers?"
In response, Mr Grayling said: "I absolutely understand her concern, it's a very busy weekend and these things are very difficult to judge, getting it right. I share some of her anxieties.
"I have asked the Rail Minister to look with Network Rail at whether there are any further ameliorations that can be made that weekend to ease the pressure, and I will ask the train companies and Network Rail going forward to try and be careful to avoid some of the busiest peak weekends.
"You have to use Christmas and Easter but I do understand her issue about the August bank holiday.
Separately, a Labour MP claimed in the Commons that Mr Grayling would also "make a mess" of Labour transport policy.
The Transport Secretary, dubbed "failing Grayling" by critics, was mocked in the Commons during question time for his department - in what could be his final appearance at the despatch box in the role before Theresa May's successor as prime minister takes over.
After Conservative Sir Geoffrey Clifton-Brown (The Cotswolds) asked Mr Grayling for his assessment of Labour's policy on roads, Speaker John Bercow intervened to say: "We're talking about Government policy.
"If the Secretary of State wants to say something about Government policy he can but he can't ruminate or pontificate on Opposition policy. It's not a matter for the Secretary of State."
Labour MP Clive Betts (Sheffield South East) then joked: "He would make a mess of that as well."
Shadow transport minister Karl Turner later said: "It's a sad day because rumour has it that it's the Secretary of State's last outing at the despatch box.
"But he is the gift that just keeps on giving - but it's not funny because he's cost the country billions."
Labour has called for railway maintenance to be "brought back in-house" after the recent deaths of two workers.
Shadow transport minister Rachael Maskell, MP for York Central, urged the Government to ban zero-hours contracts being used by rail maintenance firms to end "exploitative and unsafe work practices".
Michael Lewis, 58, and Gareth Delbridge, 64, were killed when they were hit by a passenger train on July 3 while working on tracks near Port Talbot in South Wales.
Mr Grayling said that, although the UK has "one of the safest railways in the world", this should not lead to complacency.
During Transport questions, he told MPs: "I hope that the thoughts of the whole House will be with the family, friends and colleagues of the two Network Rail staff who lost their lives in the tragic accident in South Wales two weeks ago.
"There is an ongoing investigation into what happened and I have already asked both the Accident Investigation Bureau and also Network Rail to ensure that lessons are properly learned from that tragedy."
Ms Maskell said a report into another recent fatal incident involving a worker on the railway described "Victorian methods of protections brought about by casual labour and a zero-hour culture".
She asked: "Will the Secretary of State bring an immediate end to zero-hour contracts, as advised by the regulator for Road and Rail, bring this work back in-house, and bring an end to these exploitative and unsafe work practices?"
Mr Grayling responded: "I defend no unsafe work practices on the railways. I agree with her that the railways should always aspire to the highest safety standards.
"She should remember that we do have the safest railway in Europe, but I'm very clear from my earlier remarks that lessons need to be learned when things go tragically wrong as they have on the small number of occasions in recent years.
"I expect changes to be made as a result of the lessons that are learned from those tragic incidents."