ENTABENI SAFARI CONSERVANCY, South Africa—In the pink post-dawn light, nearly 300 runners stretched and limbered up, some nervously chattering, some focusing silently on the task ahead—running 26.2 miles in a game reserve filled with the five most-difficult African species to hunt: rhinoceros, leopard, buffalo, elephant and lion.

“Guys, when you see a ranger with a rifle, that means that something could be quite close by,”J.P. Meyer, the jovial and khaki-clad general manager at Honeyguide Ranger Camp, said during a briefing the day before the 12th running of the Big Five Marathon in June. “If our rangers do tell you, ‘Please, get on the vehicle,’ there’s a reason for it. Something brown and furry is joining the marathon.”

It wasn’t an idle threat. Later that night, a lioness killed a wildebeest on a section of the runners’ route, forcing organizers to scramble and reroute 1.5 miles of the course.

South Africa’s Big Five Marathon is part of a fast-expanding pantheon of ultra-endurance races that include marathons along the Great Wall of China, in Antarctica and along Peru’s Inca Trail. As long-distance running has exploded in popularity, runners and companies that organize races have been thinking up increasingly challenging contests, from 100-plus-mile ultramarathons through the desert to the World Marathon Challenge—seven marathons on seven continents in seven days, a feat accomplished by 26 runners to date.

 

“The bragging rights of saying you’ve done a marathon ain’t cutting the mustard anymore,” said ultramarathoner Tobias Mews, author of “50 Races to Run Before You Die.” “People look for something that sounds a bit more impressive, that would make a better story.”

For runners from Japan to Brazil to Poland who come to compete alongside Africa’s Big Five—the race provides the inimitable thrill of trying to avoid becoming lunch.

“I hope I don’t get eaten,” said Rosetta Steeneveldt, 46, of Trondheim, Norway, the night before the race as she loaded her dinner plate with pasta. After the race, the South African native was covered in dust, exhausted. “I did it,” she said, brandishing her finisher’s medal.

So far, no marathoner has ever been injured by an animal, but brushes with the big five’s smaller cousins happen regularly. Emile Hunter ramped up training before her college graduation trip to South Africa, where she would run the race with her parents, who are attempting to run a marathon on each continent over a few years. A couple days before, monkeys got into her room through an open window and ate all of her energy chews.

“My Crest white strips, my toothpaste…the powder from my drink mix was everywhere,” said the 25-year-old who lives in San Antonio. “My mom was shouting at them, and I was kicking the curtains to make sure there weren’t any more hiding in them.”

 

This year, dozens of runners were cut off by herds of galloping wildebeest and blesbok antelope, which kicked up huge clouds of dust in their wake. Runners on either side oohed and aahed, excitedly snapping pictures and selfies with their smartphones.

The race, run by Danish travel-running company Albatros Adventure, isn’t the only game-park marathon. Kenya’s Safaricom Marathon, a charity event now in its 17th year, attracts about 1,400 runners. Two helicopters clear the course of big game before the start.

The race here is capped at 300 runners, who brave a steep mountainside climb. Big Five Marathon times are typically far off personal bests, and this year, 12 of 140 starters in the full marathon failed to complete the course within the seven-hour time limit.

“This was the hardest physical challenge of my life to-date,” said Ms. Hunter’s monkey-scolding mother, Barbara. “It’s a bit like childbirth. At first I told [my husband] there was no way I would do that again,” she said. “But this morning I was thinking maybe I’d do the half” marathon option.

A lot of planning goes in to making sure the biggest physical challenge of the race remains simply completing it.

“The rhinos and elephants have a tendency to pull off a lot of the signs [marking the course], and it can actually be a matter of life or death if you make a wrong turn,” said Lars Fyhr, head of Albatros Adventure Marathons. “You just know if you run into a lion…yeah. The race is closed.”

To avoid that scenario, rangers head out the night before the race to track down the park’s resident lions and stay with them until the last runner is picked up or across the finish line. Some 30 rangers, in addition to the park’s game-management team, are deployed on race day, to make sure runners and the big five stay separated.

“We are in their space, so we must respect them,” said Trevor Mthunzi, head ranger on race day this year.

Mr. Mthunzi spent race day with some of Entabeni’s hippos, which kill about five times more people world-wide a year than lions, according to the Gates Foundation.

“From the first runner coming through, they were like, ‘What’s happening here?’ ” Mr. Mthunzi said of his hippo charges, who wiggled their ears and grunted in the dam behind him. “Of course, they’re excited to see human beings running on the ground.”

Near the hippo ponds, the park’s game-management team carefully monitored a cheetah—the world’s fastest land animal, who can clock speeds of 60 miles an hour—who unbeknown to the runners, was lazing about just 300 meters from the course.

 

This year’s race wasn’t completely without incident. Rashaad Forehand, 38, of San Diego, was running down the course’s steep mountainside when he heard something rustling in the bushes to his right.

“I turned back, tripped on a rock and I hit my head on another rock,” he said afterward. “It didn’t hurt when it hit, but I saw all of this blood.”

Luckily, the noise Mr. Forehand heard was a ranger, not one of the big five.

“You think, ‘It could be something,’ ” he said, especially after hearing “distinct growling” during a training jog the morning of the race. “You never know.”