故事开始于卡特曼家中，许多各种打扮的孩子们在一起讨论新一轮游戏的主题，克莱德坚决反对精灵——人类战争的主题；肯尼提出的外星——机械主题托肯很接受，但被众人反对；凯尔也试图提出犹太人——基督教徒的主题，但却遭到了所有人的反对。最终，卡特曼从厨房走出，一锤定音决定，玩牛仔——印第安人主题。
特维克表示反对，因为牛仔老是输，但卡特曼推荐了一名“一直在玩手机”的新小孩（官方解释为傻缺，但其行为略有出入，有待考证），称他必将扭转战局。于是卡特曼用视频联系了新小孩——也就是玩家，让他参加这场游戏。
至此，南方公园的全民大战游戏——手机毁灭者，正式开幕！
主线
主线是游戏剧情的体现。在这个模式中，玩家面对的是电脑，为单人PVE
主题
在不同的区域会有不同的主题，如探险、科幻、神话、奇幻等等，详见主题条目。在不同的主题中，对手（主要是小怪）的形象将会有所不同，所用的技能也会不同，比如科幻主题中有些小怪会使用冰冻技能，神秘主题中有些小怪会操纵能量等。
关卡
关卡按照主题顺序排布，以章节作为分界线，每个章节有五个关卡，每个关卡有十五次奖励，共75次。
每个关卡有十五个难度，难度循序渐进，以下方的难度表盘作为说明（但难度困难指数表就已达到最大也不见得打不过），每打二十五次，章节就会升级，其中的关卡的掉落物品也会变得更好。达到50/75级之后，将有概率出金卡。每个关卡过关十五次后将无法得到奖励，但难度仍会继续上升。
每个章节首次破关会获得服装等额外奖励。
关卡列表
| Episode | Stage | Featured Enemies | Boss |
|---|---|---|---|
| 1 - 印第安夏日 Indian Summer |
1 | Indian Brave Indian Hunter |
Inuit Kenny |
| 2 | Indian Hunter Indian Brave |
Storyteller Jimmy | |
| 3 | Indian Brave Indian Hunter Indian Brute |
Shaman Token | |
| 4 | Indian Brave Indian Hunter Indian Brute |
Medicine Woman Sharon | |
| 5 | Indian Brave Indian Hunter Indian Brute |
Pocahontas Randy | |
| 2 - 众月要塞 Many Moon's Stronghold |
1 | Arrow Tower Indian Brave Indian Hunter Indian Brute Inuit Kenny |
Hookhand Clyde |
| 2 | Indian Brave Indian Brute Indian Hunter Smuggler Ike Captain Wendy |
Pirate Ship Timmy | |
| 3 | Arrow Tower Indian Brave Indian Hunter Rat Swarm Barrel Dougie |
Deckhand Butters | |
| 4 | Indian Brave Barrel Dougie Indian Hunter Mimsy |
Nathan | |
| 5 | Arrow Tower Indian Brave Shaman Token Indian Hunter Deckhand Butters Smuggler Ike Barrel Dougie Pirate Ship Timmy Hookhand Clyde Captain Wendy |
Stan of Many Moons | |
| 3 - 次世代街头 The Cyber-Ghetto |
1 | Rat Swarm Space Grunt Space Gunner Cyborg Titan |
Astronaut Butters |
| 2 | Toxic Pylon Space Grunt Space Gunner Cyborg Titan Enforcer Jimmy Warboy Tweek Ice Sniper Wendy |
Alien Clyde | |
| 3 | Space Gunner Enforcer Jimmy Space Grunt Cyborg Tower Rat Swarm |
Alien Queen Red | |
| 4 | Space Grunt Space Gunner Cyborg Titan Warboy Tweek |
Gizmo Ike | |
| 5 | Alien Clyde Astronaut Butters Ice Sniper Wendy Program Stan Space Warrior Token Warboy Tweek |
Cyborg Kenny | |
| 4 - 外星垃圾场 Alien Junkyard |
1 | Space Grunt Space Gunner Rat Swarm Warboy Tweek Underpants Gnomes Cyborg Titan |
Sixth Element Randy |
| 2 | Pigeon Gang Space Grunt Space Gunner Astronaut Butters Cyborg Titan Cyborg Tower Toxic Pylon |
Bounty Hunter Kyle | |
| 3 | Space Grunt Space Gunner Turbo Space Grunt Cyborg Titan Enforcer Jimmy Alien Clyde Rat Swarm |
Space Warrior Token | |
| 4 | Turbo Space Grunt Space Gunner Warboy Tweek Cyborg Titan Space Grunt Pigeon Gang |
Ice Sniper Wendy | |
| 5 | Alien Clyde A.W.E.S.O.M.-O 4000 Ice Sniper Wendy Marine Craig Program Stan Space Warrior Token Warboy Tweek |
Cyborg Kenny | |
| 5 - 改造人指挥中心 Cyborg Command Center |
1 | Space Grunt Space Gunner Enforcer Jimmy Subzero Titan Rat Swarm Astronaut Butters Alien Clyde |
Program Stan |
| 2 | Toxic Pylon Space Grunt Space Gunner Cyborg Titan Alien Clyde Astronaut Butters |
Marine Craig | |
| 3 | Space Grunt Space Gunner Turbo Space Grunt Warboy Tweek Underpants Gnomes Ice Sniper Wendy Cyborg Tower Cyborg Titan |
Mecha Timmy | |
| 4 | Space Grunt Turbo Space Grunt Space Gunner Cyborg Titan |
Powerfist Dougie | |
| 5 | Cyborg Tower Pigeon Gang Space Grunt Space Gunner Rat Swarm Astronaut Butters Alien Clyde Warboy Tweek Cyborg Titan Mecha Timmy Ice Sniper Wendy Program Stan |
Cyborg Kenny | |
| 6 - 神话觉醒 Mystical Awakening |
1 | Mormon Missionary Zionist Ranger |
Youth Pastor Craig |
| 2 | Mormon Missionary Zionist Ranger Little Choirboy Astronaut Butters Enforcer Jimmy |
Poseidon Stan | |
| 3 | Mormon Missionary Little Choirboy Zionist Ranger Holy Defender |
Witch Doctor Token | |
| 4 | Little Choirboy Enforcer Jimmy Underpants Gnomes Zionist Ranger Poseidon Stan Mormon Missionary |
Imp Tweek | |
| 5 | Angel Wendy Friar Jimmy Pope Timmy Poseidon Stan Prophet Dougie Sexy Nun Randy Witch Doctor Token |
The Master Ninjew | |
| 7 - 圣洁之路 The Holy Road |
1 | Healing Fountain Zionist Ranger Little Choirboy Underpants Gnomes Enforcer Jimmy |
Choirboy Butters |
| 2 | Underpants Gnomes Little Choirboy Zionist Ranger Witch Doctor Token Mormon Missionary Poseidon Stan |
Prophet Dougie | |
| 3 | Healing Fountain Poseidon Stan Zionist Ranger Little Choirboy Mormon Missionary Pigeon Gang Underpants Gnomes |
Angel Wendy | |
| 4 | Little Choirboy Mormon Missionary Zionist Ranger Holy Defender Healing Fountain |
Poseidon Stan | |
| 5 | Energy Staff Hermes Kenny Pope Timmy Poseidon Stan Prophet Dougie Sexy Nun Randy Witch Doctor Token Zen Cartman |
The Master Ninjew | |
| 8 - 犹太忍者藏身处 Ninjew Hideout |
1 | Gizmo Ike Enforcer Jimmy Zionist Ranger Arrowstorm Caster Choirboy Butters Little Choirboy Angel Wendy Holy Defender Prophet Dougie Witch Doctor Token Mormon Missionary |
Hermes Kenny |
| 2 | Witch Doctor Token Zionist Ranger Little Choirboy Pigeon Gang Mormon Missionary Arrowstorm Caster Healing Fountain Rat Swarm Choirboy Butters |
Friar Jimmy | |
| 3 | Zionist Ranger Gizmo Ike Little Choirboy Space Grunt Alien Queen Red Nathan Mormon Missionary Angel Wendy Underpants Gnomes Astronaut Butters |
Sexy Nun Randy | |
| 4 | Mormon Missionary Rat Swarm Little Choirboy Zionist Ranger Angel Wendy Underpants Gnomes Lightning Bolt Caster Hermes Kenny Poseidon Stan Friar Jimmy Pigeon Gang Imp Tweek |
Pope Timmy | |
| 5 | Mormon Missionary Friar Jimmy Zionist Ranger Angel Wendy Rat Swarm Choirboy Butters Hermes Kenny Poseidon Stan Little Choirboy Pope Timmy Imp Tweek Prophet Dougie Sexy Nun Randy |
The Master Ninjew | |
| 9 - 龙腾之境 Dragon Pass |
1 | Castle Defender Squire Native Hunter Crusader Rat Swarm |
A Rat |
| 2 | Little Choirboy Squire Native Hunter Deckhand Butters Rat Swarm Subzero Titan Rogue Token |
Princess Kenny | |
| 3 | Castle Defender Squire Native Hunter Crusader Little Choirboy Sexy Nun Randy Underpants Gnomes Turbo Space Grunt Nathan Pigeon Gang |
Le Bard Jimmy | |
| 4 | Squire Cyborg Kenny DogPoo Big Gay Al Native Hunter Gizmo Ike Storyteller Jimmy |
Shieldmaiden Wendy | |
| 5 | Canadian Knight Ike Catapult Timmy Dark Mage Craig Dwarf Engineer Dougie Dwarf King Clyde Kyle of the Drow Elves Le Bard Jimmy Princess Kenny Robin Tweek Rogue Token Stan the Great The Amazingly Randy |
Grand Wizard Cartman | |
| 10 - 兽人之渊 The Orc Pit |
1 | Little Choirboy Le Bard Jimmy Castle Defender Healing Fountain Native Hunter Nathan Crusader Underpants Gnomes Marine Craig DogPoo |
Robin Tweek |
| 2 | Castle Defender Squire Princess Kenny Native Hunter Healing Fountain Le Bard Jimmy Turbo Space Grunt Shieldmaiden Wendy Rat Swarm Subzero Titan Little Choirboy Pigeon Gang |
Kyle of the Drow Elves | |
| 3 | Pigeons Cocks Arrowstorm Caster Lightning Bolt Caster |
The Amazingly Randy | |
| 4 | Pigeon Gang Cocks Barrel Dougie Native Hunter Castle Defender Toxic Pylon Healing Fountain Arrowstorm Caster Underpants Gnomes Crusader |
Rogue Token | |
| 5 | Canadian Knight Ike Catapult Timmy Dark Mage Craig Dwarf Engineer Dougie Dwarf King Clyde Kyle of the Drow Elves Le Bard Jimmy Princess Kenny Robin Tweek Rogue Token Stan the Great The Amazingly Randy |
Grand Wizard Cartman | |
| 11 - 精灵圣殿 Elven Sanctuary |
1 | Storyteller Jimmy Native Hunter Underpants Gnomes Squire Shieldmaiden Wendy Arrowstorm Caster Gizmo Ike Lightning Bolt Caster The Amazingly Randy |
Dwarf Engineer Dougie |
| 2 | Underpants Gnomes Native Hunter Cocks Pigeon Gang Squire Crusader Toxic Pylon Nathan Robin Tweek |
Canadian Knight Ike | |
| 3 | Castle Defender Underpants Gnomes Pigeon Gang Healing Fountain Canadian Knight Ike Crusader Native Hunter Barrel Dougie Squire Rat Swarm Princess Kenny Dwarf Engineer Dougie Robin Tweek |
Stan the Great | |
| 4 | Squire Underpants Gnomes Stan the Great Native Hunter Cocks Crusader Princess Kenny Robin Tweek Rat Swarm Kyle of the Drow Elves Canadian Knight Ike Shieldmaiden Wendy |
Dwarf King Clyde | |
| 5 | Canadian Knight Ike Catapult Timmy Dark Mage Craig Dwarf Engineer Dougie Dwarf King Clyde Kyle of the Drow Elves Le Bard Jimmy Princess Kenny Robin Tweek Rogue Token Shieldmaiden Wendy Stan the Great The Amazingly Randy |
Grand Wizard Cartman | |
| 12 - 巫师王的城堡 Grand Wizard's Castle |
1 | Cocks Squire Underpants Gnomes Rat Swarm Rune Totem Native Hunter Crusader Princess Kenny Space Grunt Robin Tweek Catapult Timmy |
Shieldmaiden Wendy |
| 2 | Rat Swarm Squire Mimsy Rune Totem Crusader Arrowstorm Caster Native Hunter Robin Tweek Shieldmaiden Wendy Cocks The Amazingly Randy Kyle of the Drow Elves Stan the Great |
Catapult Timmy | |
| 3 | Crusader Rogue Token Squire Castle Defender Healing Fountain Native Hunter Mimsy Nathan |
Princess Kenny | |
| 4 | Toxic Pylon Castle Defender Healing Fountain Squire Underpants Gnomes Pigeon Gang Rune Totem Native Hunter Dwarf Engineer Dougie Canadian Knight Ike The Amazingly Randy Crusader Catapult Timmy |
Dark Mage Craig | |
| 5 | Native Hunter Squire Canadian Knight Ike Pigeon Gang Cocks Rat Swarm Dark Mage Craig Castle Defender Cyborg Titan Lightning Bolt Caster Rune Totem Dwarf King Clyde The Amazingly Randy Catapult Timmy Rogue Token Shieldmaiden Wendy Robin Tweek Stan the Great Kyle of the Drow Elves |
Grand Wizard Cartman |
超级英雄主题
超级英雄主题具有独立的附加剧情，一共八关，必须完成主线的第13小关后才能进行。每关首先要完成四个模块的任务，然后才能进行并获取一次性奖励。完成后会送新主题首批放出的所有金银卡牌各一张以及升级材料。视频和剧情流程参见av60351818
剧情梗概：卡特曼在推销他的传奇卡片浣熊侠，要求主角去招募其他的超级英雄以获取这张金卡。途中卡特曼假装卡片被偷走并栽赃电话女侠温蒂，最后被发现其实浣熊侠并不是传奇卡，温蒂才是，遭到众人的嘲笑。