The Cajun Navy is back to fight the war against pythons invading the Everglades. King of the Swamp Troy Landry, along with his son Chase and snake expert Bill Booth, track serpents into a breeding ground known as Deer Haven. Meanwhile, veteran swamper Bruce Mitchell and invasive species hunter, Zak Catchem, take on the legendary Skunk Ape Alley, an area known for strange encounters and massive pythons.

As the hunting season heats up, Troy, Chase and Bill dive into deep water to catch pythons, but might be in over their heads. Meanwhile, Bruce and Zak fear they've bitten off more than they can chew when they venture into Viper Jungle, an area filled with venomous rattlesnakes and moccasins.

The hunters venture into the Everglades Triangle, an area known for mysterious disappearances and swarms of snakes; Troy, Chase and Bill use a drone to search the swamp from the air, while Bruce and Zak track snakes with a handheld thermal device.

When Troy, Chase and Bill mount an airboat to hunt an area pythons are raiding alligator nests, an unfortunate mishap could leave them stranded overnight. Meanwhile, Bruce and Zak's journey into an abandoned ghost town with a haunted past, leads them to an unexpected opportunity.

Troy, Chase, and Bill gamble on a long journey into the center of the Everglades, following the migration of giant pythons to the furthest depths of the wetlands. Meanwhile, Bruce and Zak head deep into outlaw country, looking for snakes hiding on a deserted bootlegging trail...but what they uncover is far more shocking than they expected.

A friendly wager on which team can catch the most snakes and the biggest python; Troy, Bill and Chase return to a honey hole from last season, while Zak and Bruce place their bets on an abandoned Cold War bomb shelter.

As a heat wave grips the Everglades, Bruce and Zak call in canine reinforcements to sniff out serpents hiding from the rising temperature. Meanwhile, Troy, Chase, and Bill hunt the remote jungles of snake island. But when a differing opinion on strategy divides them, Troy soon finds himself alone in the middle of nowhere.

All five hunters converge on the northern edge of the Everglades to stop the invasion of serpents into a critical bird sanctuary.