Park made her official acting debut in the 2006 high school television series Secret Campus alongside fellow newcomer Lee Min-ho. Among the notable projects during the early stage in her career are the historical epic The King and I and Peabody Award-winning teen drama Jungle Fish with Kim Soo-hyun, based on a true story that depicts the pressures placed on students to achieve and gain admission to prestigious colleges and universities.

Park rose to fame after starring opposite Cha Tae-hyun in comedy Scandal Makers, which drew 8.3 million viewers to become the number one top grosser of 2008 and one of Korean cinema's biggest hits. Described by Variety as "excellent" in her role as a spunky teenage mom, Park's much-praised performance swept Best New Actress awards in 2009. She has been dubbed as "Nation's Little Sister" because of its success. She then starred in a short film directed by Lee Hyun-seung, human rights-themed omnibus If You Were Me 4 in 2009.

However, in 2010 she became involved in a series of legal disputes with her then-management agency and a film production company, causing the Actress to be tied up in lawsuits and unable to work for the next few years.

After she was designated the promotional ambassador (called "PiFan Lady") for the 2011 Puchon International Fantastic Film Festival, Park finally ended her four-year absence from the limelight by headlining the 2012 horror thriller Don't Click. Later that year, she starred alongside Song Joong-ki in fantasy romance film A Werewolf Boy, which surpassed 7 million admissions to become one of the most successful Korean melodramas of all time. The song her character sings in the film, "My Prince", was released as a digital single and included in the movie Soundtrack.

In 2013, Park joined the cast of Law of the Jungle, a reality-documentary program featuring Comedian Kim Byung-man and several celebrities as they explore and survive the New Zealand wilderness.

In a departure from her previous sweet, innocent characters, Park played the tough, potty-mouthed leader of her high school gang in Hot Young Bloods (2014), a teen romantic comedy set in the 1980s. Park, who was born in North Chungcheong Province, said she had fun swearing in southern dialect, though she found it difficult to master, being a mixture of Jeolla and Chungcheong dialects.

In 2015, she headlined the mystery thriller The Silenced, set in a girls' boarding school during the Japanese occupation. This was followed by dual roles in romantic comedy Oh My Ghost, Park's first television series in seven years. Her salary of ₩30 million (US$27,000) per episode made her the highest paid Actress to appear on cable channel tvN. The series was a commercial and critical hit, and garnered the Best Actress award for Park at the 4th APAN Star Awards. She was also dubbed as the "romantic comedy queen" by the Korean press.

In June 2016, Park was cast as the title role in JTBC's series Strong Woman Do Bong-soon, premiered in February 2017, where she played a character with superhuman strength. The series became one of the highest rated Korean dramas in cable television history. Due to its popularity, it earned her Korea Reputation Center's highest brand value among Korean TV actors and the highest consumer participation rate in February and March 2017.

Park Bo-young's ankle ligaments were torn during a workout before shooting began for TV series Strong Girl Bong-soon. In April 2017, the hospital advised her to wear a cast but she had to use ankle tape and started out with physical therapy instead, due to the ongoing filming. Two months after wrapping up the series, she underwent a minor 20-minute surgery. On September 6, her agency stated that the Actress was in the final stages of rehabilitation and would start filming Your Wedding later that month.