Writing in the Washington Post newspaper, she describes the separation of children from their parents as cruel, immoral and heart-breaking.
Her comments follow growing controversy over President Donald Trump’s “zero-tolerance” immigration policy.
Earlier Melania Trump made a rare statement expressing concern.
Mrs Trump “hates to see children separated from their families”, her spokeswoman said.
She repeated her husband’s call for “both sides” to work on immigration reform as a solution. However, fact-checkers point out that the policy was introduced by Mr Trump’s attorney general and does not require congressional action to be stopped.
Adults who try to cross the border outside of official entry points – many planning to seek asylum – are placed in custody and face criminal prosecution for illegal entry.
As a result, hundreds of children and babies are now being housed in detention centres, including warehouses and converted supermarkets, and kept away from their parents.
The first ladies’ comments come amid growing alarm over the impact of the policy.
On Monday, UN human rights chief Zeid Ra’ad al-Hussein called on the US to end what he called its “unconscionable” strategy of forced separations.
President Donald Trump had previously tried to blame the policy on Democrats, but over the weekend his secretary of homeland security, Kirstjen Nielsen, flat-out denied that such a policy existed.
“We do not have a policy of separating families at the border. Period,” Nielsen tweeted.
But the Department of Homeland Security does separate children from their parents at the border, and it just put out a press release about it on Friday, explaining its new “zero tolerance” policy for border crossers.
On Sunday, Democratic lawmakers visited shelters and processing facilities in New Jersey and Texas, demanding to see detainees.