The cartoon opens with the Road Runner (Accelerati Incredibilus) being chased by the Coyote (Carnivorous Vulgaris), the action pausing while these taxon captions are displayed. Wile E. chases after the Road Runner with a knife and fork, striking and missing, and sticking the utensils into the road as the Road Runner accelerates away. He slumps on the ground and soon comes up with a new plan.
1. The Coyote attaches a spring-activated boxing glove to a large rock and hides behind it, hoping to strike the Road Runner. However, the tension in the spring causes the rock and Wile E. to be launched backwards instead of the glove forwards. The glove then retracts backwards and punches the stunned Coyote in the face.
2. Wile E.'s next plan is to traverse a tightwire and drop an anvil on the Road Runner. The anvil proves too heavy for the tightwire to handle, and Wile E. is stretched all the way to the ground and can be seen by the Road Runner, who taunts him before dashing off. Wile E. drops the anvil and is slung up into the air. Wile E. points expectantly at his backpack and pulls out a cord, hoping for a parachute; however, upon opening the pack, there is no parachute, simply common items like a hatchet and kitchen utensils. His expression darkens, and he produces a cartridge of ACME-branded aspirin, taking a few to alleviate the inevitable pain. He weakly waves at the camera as he takes the plunge.
3. The Coyote's next plan is to set out a water glass with two signs by it reading "Last Water for 300 MILES" and "Free Drink of Water". The glass is attached by string to a TNT device. Wile E. hides as he hears the approaching Road Runner, who stops at the water stand, but simply ignores the trap and speeds behind the hiding Coyote bearing a sign that reads "ROAD RUNNERS CAN'T READ AND DON'T DRINK". The furious Coyote chases the Road Runner into a mine, but soon realizes he has no helmet or flashlight. He returns to the cap rack and dons a cap, and the Road Runner pulls up to him and provokes a chase through the mine. The audience's viewpoint cuts alternately between a view inside the mine and a Pac-Man style map view of the mine, the lights on the characters' caps color-coding their wearers in the latter period (green for Road Runner and red for Wile E.). After breaking his headlamp, Wile E. lights a match for light, but happens to be in a tunnel laden with explosives, which detonate, the explosion warping some cacti above ground into the word "YIPE!"
4. Back on the surface, Wile E. has loaded himself on a springboard in order to sling himself towards the passing Road Runner. When he cuts the rope holding him back, he is planted directly on the ground and the spring unfurls like a Slinky.
5. The Coyote is now waiting for the Road Runner to make a turn so that he can chase him with an abstrusely designed rocket. He lights the fuse with perfect timing, but unfortunately, the rocket fires directly up into the sky and explodes into an "EAT AT JOE'S" sign.
6. In the next scene, Wile E. attempts to use ACME's rocket-powered roller skates to chase the Road Runner. When the road takes a turn, however, the Coyote is propelled off the end, and finds himself briefly stranded on top of a high plateau, before being thrown up into the sky. As he falls, Coyote begins to pray and pulls out an "R.I.P." wreath before crashing into the ground. An exhausted Wile E. climbs out of the hole and spots the "Free Drink of Water" stand from before. Anxious to quench his thirst but completely forgetting that this was the trap set earlier in the cartoon, he lifts the glass and the TNT explodes.
7. In the final scene, the fully recovered Coyote places a small railroad track, two bushes, himself, and an "R.R. STOP" sign in the middle of the road. This fails to stop the Road Runner, who mows down the Coyote and leaves him spread-eagled on the track to be flattened again by a train which appears on the track. The Road Runner relaxes on the balcony of the caboose, with a sign written as "THE END" attached to the caboose.