I'd like to see her lose to something unexpected. The whose haki is bigger pissing contests are not as entertaining as crazy specific counters.
I mean, he might, because this is OP and Luffy is kind of overpowered (I really don't think he should have even made a dent in BM's army, personally), so it might happen, but I don't want it to.
First off, just in terms of haki pissing contests, Big Mom should have an advantage here period. All the Yonko should.
Second, this is her place of power and she has all her underlings here, including the commanders which Luffy was just barely able to beat one of. Meanwhile, Luffy is running with the weaker half of his crew and only Sanji seems like a big enough powerhouse to even compete with everyone.
Third, her DF fruit powers just seem kind of insane. I know every fruit has a counter, but I'm not sure what the counter to "eats your soul" is supposed to be if Brook wasn't it. Nami can control the weather, so that might take care of the sun and thunder things, but it shouldn't be so easy. And of course, you also have the hat thing. And I suspect that's not the only thing she put her soul in.
Big Mom just has such a huge advantage that the only thing I would find believable is Luffy surviving Big Mom, maybe getting a few hits in here and there. But I just don't see how, if Big Mom went serious, Luffy would stand a chance as he is now.
But I still think Doflamingo would have had it in the bag if he didn't try to use his strings as weapons to hit Luffy but instead constrain him. There's just this tactical sense that OP lacks that I'm not comfortable with. Doflamingo spent the entire time getting punched across the city from Luffy's Gear 4, so he when Luffy does his King Kong Gun attack, he decides "I'm just gonna tank this bitch!" with a flimsey spider shield and those 16 bullet attacks. If he just decided to use his string clone decoy and wait him out, or atleast try to constrain Luffy so he can't move, he'd have had a much easier time defeating him, but instead he just lets it hit him directly.
If Big Mom goes stupid and just walks into Luffy's punches, then yeah maybe he does have a chance, but I really hope that's just not the case. She has so many tools at her disposal, it'd just be a shame to see her fall to the basic shit many of Luffy's opponents fall to.