After defeating Hex Hatfield in Emerald Shrine and putting the Thorned Emerald back to its place, keeping himself from being stoned, Cactus McCoy continues his job as a treasure hunter and goes to a hidden temple to find a treasure. When he is about to get the treasure, he is stopped by a completely clothed woman saying "Not so fast!". Then she says for McCoy to step away from the treasure, McCoy and the woman step closer to the treasure. They lift the treasure from the platform, activating a bobby trap that startles the woman.
McCoy uses this as a chance to run away with the treasure. While she chases him for the treasure, McCoy goes across a bridge that breaks apart when he steps on it. Then the woman tears off the cloak and reveals her wings and flies McCoy to safety. Then she tells McCoy that her name is Ella Windstorm, then she smashes the treasure and makes McCoy in tantrum who is actually not a human but a being from the Volado race. Windstorm also tells McCoy that except her, all other beings of her race were doomed and she needs that treasure to get her face back to its usual state. She says she can use some help and makes a deal with McCoy. However suddenly, another pale woman wearing a hat (who would later be revealed to be Malana Mire) comes and abducts Windstorm, as McCoy luckily escapes after he gets knocked out by Dumbbell then Popoca wakes up McCoy and McCoy follow the map.
Now it is up to him to defeat Malana Mire and all of her goons, including Alpaca Jack, the skilled llama rider and Dumbbell, a dim-witted but strong man and save Ella. When he defeats Malana Mire, she explodes in a burst and only the Serpent Blade remains. As McCoy and Ella try to escape and save themselves from the cave, Alpaca Jack calls them; as they see that Dumbbell has lifted the rock in the entrance of the cave. Then they all together escape and get on Malana Mire's boat.
The gameplay is very similar to that of the previous game. However, there are some differences:
- While in the first game, any Enemigo can be juggled infinitely, in the second game, after juggling the Enemigo 5 times, the Enemigo "flies up to the stratosphere" (as described in-game in the description for Airborne) and leaves an explosion of money behind.
- In the first game, all areas except the last and twelfth one ended as Cactus McCoy found one of the pieces of the map to the true place of the Thorned Emerald. In the second game, though, each area has its own special treasure (like Silver Scorpion or Eternal Lantern), except for the last area, which has an honor medal for saving Ella after beating it.
- In Curse of Thorns, there are always the same type of Enemigos near the end of the level. However, in Ruins of Calavera, there is a unique type of Enemigo for each area near the end of the level. They have the same bodies, but different faces and become generally stronger after every few levels.
- If the game is complete is 100%, the Serpent Blade will be unlocked.
- Punching Enemigos can now attack with their fists.
- Checkpoints are introduced in this game.
- You can carry objects without needing to drop any weapons being carried.
- Dustbin Road
- Thistle Trail
- Prickly Prairie
- Southwind Express
- Blackstone Tunnel
- Calamity Cave
- Port Scamwell
- Gridlock Canal
- Makopa Jungle
- Whiplash Rapids
- Calavera Ruins
- The initial version of the game had some glitches. These glitches could even affect the gameplay and the completion of the game. For example, the "Projectile Pro" badge could never be completed, as Ladder Spears didn't count as a throwing weapon yet. This caused finishing the game with 100% and unlocking Serpent Blade to be impossible. When many people reported this problem in the forum of Flipline Studios, Flipline worked on the game once again and created a new version of 1.03.
- Another glitch was the sound of ziplines sometimes continuing even though the zipline was already used and the level was quitted, which was said to be annoying by some players.
- (v.1.04) Punching Enemigos sometimes lift their hands in the air (as if they were about to throw something at McCoy) If McCoy interferes while the punching enemies pick up a wooden crate. They can still move around, and hitting them again will make them stand in place As a result, these Enemigos could not be defeated by shooting or throwing weapons. Instead, melee must be used.
- In Area 5, a clip detection glitch allows McCoy to travel through a wall. (https://www.youtube.com/watch?v=cY1_f1yiQfs)
- In Area 3, at the end of the level, in the battle with the Snap Dragons, if you don't kill the 3rd Whipping enemigo when the last Punching enemigo is dead, the door will be opened, but the Whipping enemigos will still be alive, you don't need to kill him.
Despite its lately fixed glitches, Cactus McCoy 2 generally received positive reviews as a flash game. It is reviewed by JayIsGames.com and on the same website it currently has a score of 4.8 out of 5.