Macdonald is known for her starring role as Alice Manning in the 2014 crime film Every Secret Thing, alongside Dakota Fanning, Diane Lane, and Elizabeth Banks.

[8][9] Regarding Every Secret Thing, Katherine Pushkar from the New York Daily News wrote, "The film actually belongs to Danielle Macdonald, effective as cruel, jealous Alice.

[11] The following year, Macdonald starred opposite Bridget Everett and Cathy Moriarty in the drama film Patti Cake$ as the titular aspiring rapper in New Jersey.

[11] In December 2017, Macdonald appeared in the Netflix comedy series Easy,[12] playing the role of a teenager who retaliates against her wealthy parents when they force her to go to church every week.

In 2018, Macdonald appeared in two Netflix films, opposite Jennifer Aniston in the adaptation of young adult novel Dumplin', by Julie Murphy;[13] and Bird Box as Olympia, a pregnant woman who tries to survive the arrival of supernatural beings that make people want to kill themselves once they see it.

Macdonald plays the character of Helen Chambers, a police officer from a country town who is sent to investigate a man who suffered amnesia after a car crash.