Although the diversity of ecosystems in the Guadalupe Mountains allows for an incredible variety of wildlife, animals are not as commonly encountered, as many people would expect. This is due primarily to hot, dry, desert conditions present throughout much of the park. Most animals in desert ecosystems are nocturnal, and are most active after dark, or during early daylight hours when conditions are much cooler. It is often easier to observe animal signs than to see the animals themselves. Look for tracks, scat, rubbings or diggings, nests and dens.

Some of the best wildlife viewing opportunities in the park are around the few permanent water sources. Smith Springs, Manzanita Spring, and McKittrick Canyon are easily accessed, and are places where animals are frequently encountered.

Mule deer live throughout the park, and are often seen browsing near the campground or along park trails. Occasionally, especially in winter months, elk may be seen grazing near springs or along the highway corridor. Other mammals that may be seen include coyotes, the gray fox, desert cottontails, black-tailed jackrabbits, ringtails, and rock squirrels. Lucky visitors will occasionally encounter a mountain lion or a pack of javalinas. Though black bears also live in the high country, they are rarely observed.

During the warmer months, reptiles are commonly seen. Lizards, such as the Chihuahuan spotted whiptail, the prairie lizard, or the collared lizard are frequently encountered as they scurry across the desert floor. Watch for the mountain short-horned lizard in the higher elevations. Rattlesnakes, like the western diamondback and black-tailed rattlesnake are often seen along many of the park trails.