Yeah, now that you mention it, there was an episode of Hopalong Cassidy where he chases another villain on horseback down the right lane of I-5.*
Before they put up that “No Animals On Foot” sign, I can’t tell you how many times I was held up by sheep herders blocking all three lanes with their flocks.
*Topper would’ve been in more episodes, but his hooves got all worn down by the asphalt. 
Central Ohio has large numbers of Amsh and Mennonite farmers who drive buggies pulled by horses. They don’t belong on an expressway so they are prohibited. The signs reading “animals” generically probably does so to prevent someone trying to get away with a team of oxen or similar loopholes.
One of my Facebook friends, who lives in rural Colorado, posted a picture of a peculiar sign near his home. It was a yellow diamond with an upside-down picture of a cow, and he thought it might be a mistake.
Another FBF of his who had worked in the livestock industry asked if there was a feedlot or other large cattle operation nearby. He replied that there was, and told him that that when cattle die on a feedlot, an employee will drag them, or carry them in a front-end loader, to the side of the road, and then call the rendering company to pick them up at this location.
Not really a highway, but no matter where you are or which direction you’re driving in Bangkok, you’ll periodically come across a street sign saying the airport is in that direction. It’s really comical. Sure, the airport is in that direction, IF you make a few turns and a U-turn or two, yeah, you’ll get there eventually.
Except that I’m talking about interstate-like state highways, not two lane highways out in the boonies. Nobody in their right mind is going to drive 25 mph on a four lane, limited access freeway.
Now, see, I’d have assumed it meant “Watch out for falling cows.”
This may be why they don’t let me drive any more.
I once saw a sign on a rural Wisconsin road that read “Trucks Hauling”. What else would trucks be doing?
About 30 years ago, I saw a comedian who said she passed a sign on the road that said “orange cones mean men at work.” “Huh! I thought it meant psychedelic witches embedded in pavement!”
Bridge probably not icy, give it a shot.
Here’s one I saw. You’ll have to zoom in to the yellow sign to read it.
I’m not sure how to react when I’m doing 70-80mph and see a sign that reads “Airplane Crossing Ahead”.
Driving empty?
I once saw an official highway sign in San Diego that said “Cruise Ships use Airport Exit”.
Airplanes Use Boat Launch?
Not actually a highway sign, but I saw a trail sign at a state park in Maui that appears to direct you to “Ancient Burial Airport”.
Crash went the Chariots of the Gods, I guess.
Were there any services between the town and the sign? 
Alberta Highway 41 leaves the Trans-Canada Highway east of Medicine Hat, and goes straight south across the limitless treeless prairie rangeland to the US border at Wild Horse, Alberta/Dead Horse, Montana.
In 1994, we were on the kind of great transcontinental drive that everybody should do once in their life, and we were driving south on Hwy 41, and just past the settlement of Elkwater, we came to a sign that said, “No services or residences next 137 km”. I guess that was their way of saying, “If you break down much past here, especially in winter, you are screwed. Especially since the border posts aren’t open 24/7!”
We continued driving south, and the road became narrower and rougher, until I started to get a little worried. There was nothing around us but the wind, and grassland that stretched off to the horizon. Eventually we came around a curve and there were the border posts spread out before us, one on either side of a page-wire fence.
The Canadian post was a set of pretty white-painted frame houses. The US post looked like an old gas station with a 1960’s suburban house next to it.
We crossed the border, and were inspected and quizzed, and continued south across the vast empty prairie. The highway angled southeast another forty miles or so until we got to Havre, Montana, where we sought a motel and, as it evolved the next morning, car repairs.
Fun fact: there are nuclear missile sites just off that highway in Montana.
Right before you drive across the Strawberry River in Horseshoe Bend, Arkansas, there was a sign that read “ROAD UNSAFE WHEN UNDER WATER” - which my Grandfather was always quick to point out was actually necessary, because just about every time it rained someone would try and drive across the road while it was under water and get washed away, making the local paper.
Also driving through Oklahoma I was always amused by “Do Not Drive Into Smoke” and (near the jail outside Stringtown) “Hitchhikers May Be Escaping Inmates”
My FBF jokingly wondered if that was what it meant.
Most 4 (or more) lane highways and freeways have signs about driving in the right hand lane except to pass. Some years ago, Minnesota put up signs saying “Slower traffic move right.” Ummmm, if I move right, won’t I eventually leave the road?
Driving thru New Mexico about a year ago, near a state prison, the signs said “Hitchhikers may be escaping prisoners.” I wondered if I should help them out and pick them up.
On the road winding up Haleaka on Maui is a sign: “Turn on headlights in clouds.”
Headlights/wipers is problematic because lights are not required when windshield washer is deployed.
Minnesota signage used to say “Motorcyclists must burn lamps”
Indiana signs warning of aircraft speed surveillance said “Watch your speed – we are”, which is is a grammatical non-sequitur, reflexive verbs not in agreement.
