Many trains have been stolen by Shock Holiday's gang where Shock Holiday is holding them hostage until the Railroad President pays a huge ransom. When Marshall Moo fails at capturing the thief, Sheriff Terrorbull challenges him to see who catches Shock Holiday first and the loser will have to leave Cowtown.

The pirate captain Longhorn Silver and his band of buccaneers have been robbing trains and causing trouble on Moo Mesa's waterways. With a gold shipment and Cody's money for new boots in their possession, Moo Montana, Dakota Dude, and Cowlorado Kid have to go to Newportleans to track these pirates down. While trying to get back the money, Cody is caught by the Masked Bull as part of his plan to work with Longhorn Silver to dispose of the C.O.W.-Boys. Now the C.O.W.-Boys must rescue Cody, reclaim the stolen loot, and defeat Longhorn Silver.

Moo Montana, Dakota Dude, and Cowlorado Kid apprehend the Cacklin Kid after he was nearly disposed of by the Baying Bunch led by Scavenger who are seeking the location of where the Cacklin Kid hid the Baying Bunch's loot. At the courthouse, Cacklin Kid gets sympathy from Judge Overrule who instructs that Moo Montana, Dakota Dude, and Cowlorado Kid to safely transports Cacklin Kid to the federal penitentiary to serve out his one year sentence. Now the C.O.W.-Boys must get the Cacklin Kid to the penitentiary safely while evading the Baying Bunch who have tricked Sheriff Terrorbull into helping them.

On Halloween, Skull Duggery returns upon emerging from the cave-in of his mine at Skull Mountain in order to get revenge on Moo, Dakota, and Cowlorado. This time, he has obtained an age accelerating spell with the help of his fellow ghosts where they start aging everything in Cowtown.

The C.O.W.-Boys get word from Warden Gordon Bordon that Billy the Kidder and his lizard henchmen Lester and Kisser have escaped from prison. When Lily's uncle Rocky gets caught in a cave-in upon finding the lost treasure of the Concudsadors, she plans to enlist Cowlamity Kate to help rescue him only to end up captured by Lester and Kisser so that Billy the Kidder can steal the lost treasure of the Concudsadors. Now the C.O.W.-Boys and Calamity Kate must rescue Lily and Rocky, apprehend Billy the Kidder's group, and recover the lost treasure of the Concudsadors.

Bat Blastagun and his gang have escaped from prison where they find a shard of the comet that created Moo Mesa outside of Cowtown. Enlisting the help of the mad scientist Dr. Wolfgang Wolfenstein, Bat Masterson uses the shard to shrink everything.

The Great Bovini's Wild West Circus comes to Cowtown, but amusement of the masses is the last thing on the mind of the ringmaster The Great Bovini as he uses a special stone to mesmerize anyone into stealing money. In order to keep the Cowinoor Diamond from being shipped to the Jersey City Museum, Mayor Bulloney, Saddle Sore, and Boot Hill Buzzard approach The Great Bovini to help them steal it which doesn't go well as Boot Hill Buzzard is unaffected by The Great Bovini's stone. Now the C.O.W.-Boys must work with Boot Hill Buzzard into thwarting The Great Bovini and freeing the townspeople from his control.

Moo Montana, Dakota Dude, and Cowlorado Kid have to deal with four masked marauders who happen to be ladies of the Sewing B. Ranch led by Barb Wire Babs (the criminal alias of Miss Barbara). As Cowlorado Kid goes undercover in Barbed Wire Babs' group, Wild Bill Barker is kidnapped as part of Barbed Wire Babs' plot to make counterfeit money.

After Cowlorado Kid was unable to catch a gold thief, he, Moo Montana, and Dakota Dude look for the thief and end up escorting a wagon train led by Rooster Cogsbull through a valley where a creature called the Cowgoyle (a cattle/gargoyle creature) dwells. To make sure that the C.O.W.-Boys meet their end and the Cowgoyle is blamed for the action, Mayor Bulloney sends Saddle Sore and Boot Hill Buzzard to get the Masked Bull to dispose of them. Following the Cowgoyle's attacks, the C.O.W.-Boys work to catch the Cowgoyle while suspecting that it might be one of the suspicious wagon train travelers.

Cowlorado Kid discovers gold in a river causing the Gold Rush on Moo Mesa which even gets Mayor Bulloney, Saddle Sore, and Boot Hill Buzzard to work on claiming the gold. Upon Boom Town being formed as part of the gold rush, the C.O.W.-Boys work to keep the settlement in line. When a claim-jumper named Big Bucks and his henchmen Digalong and Stub plot to steal everyone's gold, the C.O.W.-Boys spring into action to protect Boom Town.

In preparation for the 11th Annual Cowtown Cross Country Race, Cowlorado Kid encounters some competition Cowlamity Kate's cousin Cowleen and her horse Tornado as well as encountering his old rival Swifty Buckhorn. Fast Willy and his henchmen plan to steal Tornado so that they can rob the Pony Express with one of the packages being the trophy for the Cross Country Race. Now Cowlorado Kid and Swifty Buckhorn must put aside their differences to help Moo and Dakota catch Fast Willy and reclaim Tornado.

J.R. takes Cody Calf and Buffalo Bull to the Invention Convention on the Dixie Trixie. Using his airship, Mules Verne and his henchmen steal the Dixie Trixie so that he can force all the inventors onboard to help him take over Moo Mesa by building a giant robot cowboy that will help in his plans by starting with raiding the governor's mansion.