CSX Corp. lost about $4 billion in market value Friday after Chief Executive Hunter Harrison was placed on medical leave, a stark reversal for investors who had shrugged off concerns earlier this year about the health of the renowned railroad turnaround artist.

Mr. Harrison, 73 years old, became ill last week after one of his regular, multiday pep-talks with management, known as Hunter Camps, according to acting CEO Jim Foote. The illness “led to medical complications,” he told investors on a call Friday.

Mr....