在这部史酷比2：怪兽偷跑喜剧/动作/悬疑/家庭/奇幻/冒险片中,一位神秘人物的出现让小镇上的居民终日生活在恐惧之中，他利用一架邪恶的机器制造出了许多可怕的怪物，将它们放到镇上为非作歹。这时，就轮到“秘密公司”的诸位出马了，可摩拳擦掌跃跃欲试的沙吉（马修·里沃德 Matthew Lillard 饰）和搭档史酷比（Neil Fanning 配音）却被告知留守公司，不必参加行动。
不甘心的沙吉决定和史酷比私下里调查事件的真相，以挽回他们一败涂地的名声，没想到却闹出了一大堆的麻烦。随着调查的深入，博物馆馆长帕特里克（赛斯·格林 Seth Green 饰）带着他的阴谋渐渐浮出水面，线索显示，这一切，很可能和传说中的恶魔复仇有着千丝万缕的关联。
When Mystery, Inc. are guests of honor at the grand opening of the Coolsville Museum of Criminology, a masked villain shows up and creates havoc before stealing the costumes of the gang's most notorious villains: Black Knight Ghost, Pterodactyl Ghost and Tar Monster. Could it be that their nemesis, mad scientist Jonathan Jacobo has returned and is trying to recreate their deadliest foes? Velma has a crush on the hunk / museum curator Patrick Wisely but why is he acting so suspicious? The Mystery Gang is hard pressed to succeed this time, since pesky TV reporter Heather Jasper-Howe insists they are buffoons.
