Launchbury has been ruled out by a broken leg, with his club Wasps hoping he will recover in time for the final two rounds of the championship, while Marler has pulled out for personal reasons.
Charlie Ewels and Tom West fill the vacancies in the squad at lock and prop.
England open their campaign against Scotland at Twickenham a week on Saturday.
Eddie Jones’ squad is due to meet up at St George’s Park on Wednesday to begin preparations for the tournament.
Launchbury’s fibia stress fracture is cruel timing given he had re-established himself in England’s second row last autumn and was set to continue alongside Maro Itoje for the Calcutta Cup clash.
“We were on an artificial surface the other day for the first time and whether that has aggravated it slightly…..Joe spoke to us after that,” Wasps head coach Lee Blackett said.
“We wanted to scan it and make sure it wasn’t serious, but it’s come back like this. We fully expect him to be out for up to six weeks.
“He will stay with us and our medics and we’ll try our best to get him back for the last couple of games of the Six Nations, that’s our aim for Joe.”
Marler’s withdrawal on unspecified personal grounds stretches England’s resources at loosehead prop.
Mako Vunipola is recovering from an Achilles injury and although remaining with Jones’ squad for rehabilitation, he is expected to miss a chunk of the competition.
It leaves Ellis Genge as the senior loosehead with the uncapped Beno Obano likely to supply bench cover and West adding a third option in the 28-man squad.
“Tom fully deserves this, he’s been absolutely outstanding this year,” Blackett said of Wasps forward West.
“He’s a younger guy who has worked ridiculously hard. Props develop a fraction later than everybody else and he’s got more and more opportunities. The more of them he’s had, the more he has shone.
“I’m really happy for him. We announced our team with him in it this morning! He’ll go away and come back a better player.
“He’ll be even more determined because once players have had a bit of it, they want more. Hopefully that will benefit him and the club.”
Marler revealed on Twitter that he would miss the entire Six Nations to be with his family.
“Always grateful for the opportunity so not an easy decision, but want to do right by my family in these crazy times and won’t be meeting up with the squad for this tournament. Look forward to watching the team rip in. Go well Rose x,” he said.
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