Girl with a Pearl Earring , a novel was written to speculate about how it was made and then a movie was based on the novel.
Last Supper is what immediately came to mind, followed by Birth of Venus and possibly The Sistine Chapel. But this is very Euro-centric, of course. My criterion is mainly, would my mother and father recognize it? They don’t know art very well at all, and I would be very doubtful they’d recognize even Starry Night, much less The Scream or Guernica or Napolean Crossing the Alps (heck, I had to look that one up, and I’m not entirely sure I recognize it. I sure as heck wouldn’t be able to name it.) But certainly they know Last Supper.
MHO: The movie was incredibly boring. Don’t bother.
I’ve seen “American Gothic” in person. It’s not very big either; in this case, it was behind a rope with a security guard next to it.
Yeah - my parents were as far from art aficionados as could be, but even they knew the Last Supper - we had one of those lenticular 3-D effect ones hanging in the house when I was a kid.
Why not Rick Meyerowitz’s?
Coincidentally, I was just watching The Beat with Ari Melber and he was doing a topic on women running in '18. I noticed one candidate had a print of what to me is Rockwell’s most important painting…
Huh. Apparently I know nothing about “Blue Boy.” I’m looking up Google images of it, and I don’t recognize it all. Where is it used in pop culture? Looks like I may have found another one of my black holes of pop culture (and I actually do enjoy keeping up on pop culture and being aware of any and all pop cultural references.)
Lucy In The Sky With Diamonds, created by Julian Lennon? Everyone’s heard of it.
More seriously, Andy Warhol’s paintings of the soup can and Marilyn Munroe.
That is a piece of art that does what art is supposed to do. And from what many might consider an unlikely source.
It amazes me to think that I lived through those times. I wonder if anyone under 50 (and white) even knows what that painting means.
I’m another who would vote for Whistler’s Mother. The main reason I think it comes in second because a lot of people recognize it from Mr. Bean.
Kinda sad.
It seems likely to me that the second most famous painting is gonna be one that’s got serious pop culture chops. Las Meninas? No chance. The Last Supper? Still very low chance. The Wave? I love it, but unlikely.
The Birth of Venus and Scream have both been parodied and referenced endlessly, as has The Creation of Adam. I’d suspect it’d be one of these three (with Adam being the likeliest).
But that raises a question: what’s meant by “famous”? Is it enough to vaguely recognize the painting but not to know its name or artist or anything about it beyond one identifying feature?
A great painting, but not that famous around the world, is it?
The Luncheon on the Grass (1862) by Edouard Manet
In the top 20 I’d include A Sunday Afternoon on the Island of La Grande Jatte by Seurat which is the pointillism painting by the lake. And also A Bar at the Folies-Bergère, by Manet, the one with the bartender reflected weirdly* in the mirror.
*Or maybe not so weirdly
Best of the unmentioned… The Beheading of St John the Baptist by Caravaggio. At least from an art critic point of view it makes several top ten lists. I had the privilege to see it in person and it is simply stunning - and HUGE (370cm x 520cm or about 10ft 2in x 17ft 1in). Stopped me in my tracks.
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I think Mr Dibble was the only one to mention The Persistence of Memory and it is instantly recognizable, but few know it by name. It’s that melting clock painting by Salvador Dali. Probably another top ten.
And I’ve just been ninja’d by GuanoLad with *A Sunday Afternoon on the Island of La Grande Jatte *by Seurat. Easily his most recognizable work and a good top ten contender.
But #2 is still The Last Supper.
It was once famous enough to show up in Mad Magazine. (I thought they did an Alfred E. Neumann version, too, but I can’t find it. Found this recent one, though.) Other parodies are thick on the ground.
This must mean I’ve seen many references to it without recognizing or understanding them. Makes sense.
We need to make a new painting, combining them all - we’ll call it “Adam Is Created, Venus Is Born, … Oh No!” 
I don’t know, but I was not suggesting it as the second most famous painting, just as possibly Rockwell’s most famous in response to the bolded below.
and the coincidence that I had seen it on the TV just minutes before reading the above.
Rockwell quit working for the Saturday Evening Post, where 99% of his iconic paintings appeared, because they wouldn’t let him tackle serious subjects. That painting is what he really wanted to do at the time. The Norman Rockwell Museum is a fine small museum and will turn your head around on everything you think you know of him.
Paintings and painters run in fads like everything else. 50 years ago I’d have said the answer was Starry Night, because every college student had a print of it. Or maybe one of Escher’s prints, which were equally ubiquitous.
And I guarantee that everybody is familiar with Ad Reinhardt’s Abstract Painting No. 5 (19620 and Robert Ryman’s Twin (1965). You see them every single day without realizing it.