Heike Makatsch was born in Düsseldorf on August 13th, 1971. Her father, Rainer Makatsch, played ice hockey for Germany's national team. After starting to study sociology at university, Heike Makatsch was cast as a host for the German music television station Viva in 1993.

Two years later, she made her screen debut as the naive lover of a convicted felon in Detlev Buck's comedy "Männerpension" ("Jailbirds") - and promptly received the Young Actor Award at the Bavarian Film Awards. The following year, she was nominated for the German Film Award for her leading role in the relationship story "Obsession" (1997). There was also much critical praise for "Liebe deine Nächste" ("Love Your Neighbor!"), Detlev Buck's satire on the Salvation Army.

After a supporting role in the acclaimed WWII melodrama "Aimée & Jaguar", Makatsch convinced critics and audiences alike with "Gripsholm", in which she plays the girlfriend of famous writer Kurt Tucholsky. She then took lead roles in Doris Dörrie's drama "Nackt" ("Naked") and in the horror sequel "Anatomie 2" ("Anatomy 2"), thereby following the example of Franka Potente, who starred in the first instalment of the successful German slasher franchise.

Makatsch, who was romantically linked to British actor Daniel Craig for several years and had subsequently moved to London, also appeared in several international productions, including "Late Night Shopping" (2001), "Resident Evil" (2002) and "Love…Actually" (2003).

2005 saw Heike Makatsch's large-scale return to German cinema: The rock'n'roll antics of the mockumentary "Keine Lieder über Liebe" ("No songs of Love") were followed by "Almost Heaven", in which Makatsch – who often sings in her films – plays a German country singer who wants to go to Nashville, but eventually ends up in Jamaica instead.

She received much critical praise, a Bavarian Television Award and a nomination for the International Emmy Award for her title role in the TV production "Margarete Steiff" (2005) about the life of the famous stuffed animal manufacturer. After her leading role as an "older sister" in a crisis in Ed Herzog's highly praised independent movie "Schwesterherz" ("Twisted Sister") alongside Anna Maria Mühe, Makatsch portrays another historic character in 2009: In Kai Wessel's "Hilde" ("The Gift Horse"), Makatsch plays the legendary actress Hildegard Knef.

Her portrayal of physician and woman's rights pioneer Hope Bridges Adams-Lehmann in "Dr. Hope – Eine Frau gibt nicht auf" ("Dr. Hope", TV) garnered her a nomination at the 2010 Bavarian Television Award. Makatsch played the role of Aunt Polly in the screen adaptation of "Tom Sawyer" (2011), and also reprised it for the sequel "Die Abenteuer von Huck Finn" ("The Adventures of Huck Finn", 2012).

After director Hendrik Handloegten cast her as one of the leads in the TV horror movie "Sechzehneichen" (2012), she starred opposite Dieter Hallervorden in the 2013 theatrical release "Sein letztes Rennen" ("Back on Track"). Follwing her turns in Lars Becker's "Wir machen durch bis morgen früh" (2013, TV), the WWII drama "Die Bücherdiebin ("The Book Thief", DE/US 2014) and the coming-of age movie "About a Girl" (2014), Makatsch played a wife whose philandering husband tries to win her back in the comedy "Alles ist Liebe" (2014).

In 2016, Makatsch played the leading role of police detective Ellen Berlinger in a new branch of the "Tatort" series. After turns in "Zweimal zweites Leben" (Twice New Life, 2016) and "Fremde Tochter" (Strange Daughter"), she played the mother of a hormonally charged teen girl in "Das Pubertier – Der Film" ("Teenosaurus Rex", 2017), Leander Haußmann’s screen adaptation of the bestselling novel by Jan Weiler.    

In 2018 she played the "Tatort" investigator Ellen Berlinger for the second time, followed by a leading role as a teacher in Aron Lehmann's award-winning youth film "Das schönste Mädchen der Welt" ("The Most Beautiful Girl in the World", 2018). In the children's film "Benjamin Blümchen" ("Benjamin the Elephant", 2019) she impersonated an inscrutable building investor, in the musical "Ich war noch niemals in New York" (2019) an ambitious television presenter who is forced to follow her sprightly mother and her new boyfriend to New York.

A year later, in October 2020, André Erkau's road movie "Gott, du kannst ein Arsch sein!" ("God, You're Such a Prick!") hit theaters. In the film, Makatsch plays the mother of a teenager suffering from cancer who spontaneously takes off for Paris with a new acquaintance in a stolen car. Also in 2020, she won at the Austrian Romy Film Awards in the category of Most Popular Actress Cinema/TV Film. 

On TV, Makatsch starred in "9 Tage wach" ("9 Days Awake", 2020) as the mother of a crystal meth-addicted teenager, as an investigative journalist in the thriller "Zero" (2021) and as a combative tenant in the six-part social comedy "Herzogpark" (2022). Makatsch also continued to play police inspector Ellen Berlinger in the "Tatort" episodes set in the city of Mainz. 

In the summer of 2022, she stood in front of the camera for Veit Helmer's feature film "Akiko, der fliegende Affe," which is scheduled for release in 2025. That same year she played the witch Severa in the childrens film "Bibi Blocksberg" (2025).