Makatsch was born in Düsseldorf, West Germany, the daughter of former German national ice hockey team goaltender Rainer Makatsch. She spent several months in New Mexico in 1988 in an effort to improve her English, and later studied politics and sociology at the University of Düsseldorf for four semesters, which was followed by an apprenticeship as a dressmaker until 1994.

Makatsch’s television career started in 1993, when she was hired by music channel VIVA, hosting shows such as Interaktiv and Heikes Hausbesuche; two years later, on 13 August 1995, she became the host of the German chart show Bravo TV, aired by RTL II, a position she kept until summer 1996. In 1997, she started hosting her own weekly, late night show titled Heike Makatsch Show. However, due to bad ratings, it was cancelled after only eight episodes.

In 1995, Makatsch won the Bavarian Film Award for Best New Actress for her role in Männerpension. In 2003, she and the rest of the cast of Love Actually were nominated for the Phoenix Film Critics Society Award for Best Cast. She was nominated in 2006 for an International Emmy Award for Best Actress for her role in Margarete Steiff – A Story of Courage.

Makatsch first appeared in a film in 1996 when she starred in Detlev Buck’s Männerpension (English: “Jailbirds”). She received the Bavarian Film Award as the most talented young actor for her performance. Since then, she has appeared in several German and English language productions including the romantic comedy Love Actually (2003). She is perhaps best known for her role as Lisa Addison, Matt’s sister in the video game-based sci-fi/horror film Resident Evil (2002).

Makatsch was in a seven-year relationship with British actor Daniel Craig, ending in 2004.

She has three daughters, born in 2007, 2009, and 2015; two with Max Martin Schröder from German indie band Tomte and Der Hund Marie. She lives in Berlin.

Since 2012, Makatsch has been a testimonial for French cosmetics company L’Oréal.

Makatsch served on the jury of the Goldene Kamera awards in 2017.