Patrick Lewis, an explosives expert, is the central character and narrator of In the Skin of the Lion. It is he who ties together the stories of the various immigrant characters who settle in the burgeoning city of Toronto in the early twentieth century.

Ambrose Small (who is not a fictional figure) is a Canadian theater impresario who owned the Grand Opera House in Toronto—along with other operatic venues in various cities in Ontario. Small disappears in 1919, and his body never found. In this novel, however, his disappearance provides employment for Patrick, who becomes one of the many workers paid $4 a week to search for the missing millionaire.

Clara Dickens is a young actress and was the mistress of Ambrose Small before he disappeared. Patrick meets her during the course of his search for the impresario, and the pair soon become lovers. They carry on a mysterious, desultory love affair throughout the novel.

Nicholas Temelcoff is a Macedonian immigrant working on the Prince Edward Viaduct. One night, he rescues a nun who was blown off the bridge by powerful winds, risking his life in a daredevil leap.

Alice Gull is the name of the nun who was saved by Nicholas Temelcoff. She later abandons religious life to become a political activist. She is a friend of Clara Dickens, and she eventually becomes romantically involved with Patrick.

Caravaggio is a professional thief who Patrick helps to escape from Kingston Penitentiary—where they are both inmates. Following Patrick's release, they meet again, become good friends, and join forces in high-risk political activism. This character also reappears in another one of Ondaatje's novels: The English Patient.

Rowland Harris is Toronto's Commissioner of Public Works and the man who supervises the construction of the Prince Edward Viaduct. Later in the novel, he oversees the "Waterworks" project: a tunnel which will bring water from Lake Ontario to the city. Patrick ultimately confronts this bureaucrat concerning Harris's horrendous exploitation of the labor force.

Hana is the young daughter of Alice Gull and step-daughter of Patrick. She also resurfaces in The English Patient.