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.
Wile E. Coyote (Hard-Headipus ravenus) tries various devices to try and trap Road Runner (Speedipus rex), all of which backfire. For instance, when he tries to trick the Road Runner into an Acme Parcel-making Machine, the result is a neatly-packaged Coyote. 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 he is so relieved that he steps out without looking where he is going and strides off the other side of the cliff. 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 ABC version of this cartoon cuts a scene where Wile E. gets tangled on a cactus with dynamite. 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.