In the early 19th century, the western world trembled with fear and excitement around new medical advances. The medical horror Frankenstein was a bestselling novel, and medical shows in which physicians would electrify corpses, pull teeth, or peddle their "miracle cures" drew huge crowds.

In Trepanation, players take the role of fraudulent doctors in this era who are performing medical shows for the gullible public and vying to become the most famous medical performer.

The game takes place over six days (rounds). At the start of each day, players prepare their schedules by booking time slots at locations around town, then the day's events happen according to these schedules. Players will gather medicine and equipment, employ accomplices, bribe the police, and perform shows — but not all plans run smoothly. Other players will create stock shortages, steal your audience, and snatch up those essential time slots! Performing shows in related sets grants fame bonuses, as does getting your name in the local newspapers. Grave-robbing in the night damages your reputation, but earns cash! At the end of a busy week, the player who has earned the most fame wins.

This worker placement game features lots of action spaces because the emphasis is on timing your actions correctly to make the most of your limited resources.