Mohler, president of the Southern Baptist Theological Seminary, was speaking in response to the Obama administration's decision this week to stop defending the 1996 Defense of Marriage Act (DOMA) – federal law that defines marriage as between a man and a woman – in the courts.
Conservative groups and Christians have criticised Obama for going against his duty as president to defend the law.
"When a president takes oath of office, he's upholding ... defending the laws of the United States of America," said Mohler, who also noted that DOMA had passed as a bipartisan effort.
"The White House has clearly made a calculation that it can do this now with far less political risk than it could even two years ago."
Though Obama has always expressed his desire to repeal DOMA, his personal view on marriage had been traditional.
While on the campaign trail, running as the Democratic presidential nominee, Obama asserted his belief that marriage is the union between a man and a woman. He added, while being interviewed by Pastor Rick Warren, that "for me as a Christian, it's also a sacred union. God's in the mix".
Recently, however, he has stated that his views on gay marriage are "evolving".
The Obama administration has been pro-gay since taking office two years ago and Mohler noted that there has been a long trajectory on the issue of gay marriage pointing to this day.
With the Justice Department now pulling its defense of DOMA, pending legal challenges against the federal law will likely result with the nullification of DOMA, Mohler predicted.
"You can say, the cards are pretty much stacked against DOMA," he illustrated.
He warned that when Christians feel threatened, they have to be careful not to lash out with a predictable response.
The Southern Baptist made it clear that he was not saying that they are giving up. Marriage is still an institution Christians need to save, particularly in their own community. But Christians also need to start learning how to deal with the shifting culture and even face the fact that they may lose a few from their flock.
"I think we're going to be surprised and heartbroken over how many people are going to capitulate to the spirit of the age," he noted. "We're going to find now that there may not be as many of us as we thought."
Nevertheless, Christians must be prepared to make marriage one of the many topics where parents have to have "the talk".
"It's interesting now that the world is so morally upside down that when we talk about marriage we have to make a distinction between natural marriage – heterosexual marriage – and this new thing that people are calling marriage," Mohler said.
"We have to prepare our children to be in a context in which they're going to be in a playground with children who have two dads or two moms or who knows what kind of combination will come."
Ultimately, the worldview or the belief that God designed marriage to be between a man and a woman only makes sense if one understands the Gospel, Mohler pointed out, which raises a critical point:
"This whole situation reminds us that we are, first of all, to be Gospel people who are fellow sinners ... saved by grace, with the responsibility to share the Gospel with others."