The title is a play on the cowboy character "Hopalong Cassidy" created by Clarence E. Mulford in a series of short stories and books later adapted to film.
As usual, Wile E. Coyote (Hard-headipus ravenus) has gone in pursuit of The Road Runner (Speedipus Rex). The title shows just before the Coyote gains on the Road Runner. He lunges, leaping and grabbing his quarry by the throat. A two-second wrestling match follows, with both combatants in a round ball rolling down the road from the force of their running, but Wile E. emerges "holding" only a smoke outline of the bird. The confused coyote looks in his hands just as the Road Runner speeds up behind Wile E. He beeps, sending the Coyote flying through the air and leaves him hanging on a telephone pole. When he slides back down, the Road Runner beeps again, sending not only Wile E. in the air, but also the telephone pole, which escapes Wile E.'s grip. He then looks relieved, but because of the power lines, the pole zooms back to Wile E. and drives him into the ground. He then comes out of a nearby manhole, flattened and humiliated. Of course, there is nothing left to do but plan more schemes.
- First, the Coyote goes simple by waiting behind a rock face, and when he hears the "beep-beep" of the Road Runner, he jumps out into the middle of the road, only to be flattened by an approaching truck.
- Next, the Coyote sets up a rope and rock trap, but when he pulls the string, he ends up squashing himself (but not his feet).
- The Coyote now places dynamite in a tunnel under the road, but as he goes deeper into the tunnel, the detonator handle pushes down further, and eventually the dynamite explodes on the Coyote.
- Now, the Coyote uses an Acme Christmas Packaging Machine. He puts it in a pit with a sign that says "DETOUR". The Coyote snickers gleefully, but then the Road Runner, as expected, pops up behind the coyote and beeps. The startled Coyote leaps in the air and into the Christmas Packaging Machine. The result is a neatly packaged Wile E. Coyote. Humiliated, the boxed Coyote tiptoes off the screen.
- This time, the Coyote uses dynamite on a fishing line. When he hears the Road Runner, he jerks back the rod and prepares to cast the line. He jerks a bit too hard, however; the dynamite gets stuck in a cactus, and eventually, the Coyote gets wound around the cactus with the line. He then sees that the dynamite is about to go off, and tries to blow out the fuse, but instead makes it wear out faster, and it then explodes.
- In the cartoon's longest scene, the Coyote scatters some Acme Earthquake Pills on the road, hoping that the Road Runner will mistake them for birdseed. The Road Runner obligingly eats them, but they have no effect as he zooms away. In disgust, Coyote swallows an earthquake pill himself, and then even more disgustedly swallows all of the remaining pills. After jumping up and down several times in an attempt to trigger an earthquake, he contemptuously chucks the empty bottle over his shoulder - and immediately leaps after the bottle with bulging eyes to catch it before it shatters in the middle of the road. Too late, Coyote reads the fine print at the bottom of the bottle's label: "Not effective on Road Runners". As soon as he sees this he gulps nervously, now knowing what he is in for. As he gingerly takes his first step to get out of the middle of the road, the product takes effect on him, causing him to shake, rattle and jerk helplessly across the landscape, getting flattened by a huge boulder and almost falling off a narrow rocky arch in the process. When the product finally wears off, the Coyote is so relieved that he accidentally falls off a cliff because he fails to look where he is going. The Road Runner then beeps once more and takes off, with the trail of smoke left behind him, forming the words "The End."
- Maurice Noble's scenery changes from the yellow-sky pioneered three years earlier by "Zoom and Bored" to a blue sky, and some rock formations became off-white rather than shades of red, but many other characteristics of the "Zoom and Bored" style, such as sharp gravity-defying rock formations are retained, distinguishing this new style from that of early Road Runner cartoons such as "Fast and Furry-ous".
- The earthquake pills gag is included in the Road Runner compilation of The Bugs Bunny Road-Runner Movie.
- The earthquake pills gag happens to be the longest gag in a Road Runner cartoon.
- The ABC version of this cartoon cuts a scene where Wile E. gets tangled on a cactus with dynamite and a fishing pole. The cut makes it seem that Wile E. threw the dynamite and it exploded. Also cut was the part where Wile E. ingests the entire bottle of earthquake pills before throwing the bottle aside and reading the warning that the pills don't work on Roadrunners. However, Wile E. swallowing the one pill before this scene was left in.
- Much like the ABC version, the Nickelodeon version also cut the part where Wile E. ingests the entire bottle of pills before throwing the bottle aside and reading the warning that the pills don't work on Roadrunners. Unlike the ABC version, Nickelodeon kept in the scene of Wile E. tangled on the cactus with the dynamite.
- VHS - Road Runner and Wile E. Coyote: The Scrapes of Wrath
- LaserDisc - Road Runner Vs. Wile E. Coyote: If At First You Don't Succeed...
- Streaming - Boomerang App