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Miranda made his Broadway debut in 2008, writing the music and lyrics for and starring in the musical In the Heights, which won the Tony Award for Best Musical and Best Original Score and the Grammy Award for Best Musical Theatre Album. It was later adapted as a 2021 film of the same name. Miranda returned to Broadway in 2015, writing the script, music, and lyrics and starring in the musical Hamilton, which was praised by critics and became a widespread cultural phenomenon. Hamilton won the Pulitzer Prize and was nominated for a record 16 Tonys and 11, including Miranda's first win for  Best Book of a Musical. The Hamilton cast recording spent 10 weeks atop Billboard's Top Rap Albums chart and became the eleventh-biggest album of the 2010s.

A frequent collaborator of the Walt Disney Company, Miranda has written original songs for the studio. He won two Oscar nominations for "How Far I'll Go" & "Dos Oruguitas" from Moana and Encanto. Encanto's song "We Don't Talk About Bruno"  broke various records. It marked Miranda's first number-one song on the US Billboard Hot 100 and the UK Singles charts. He starred as Jack in the musical fantasy Mary Poppins Returns (2018), for which he was nominated for a Golden Globe. For his performance in the Disney+ live stage recording of Hamilton, which was released in 2020, he received a Golden Globe & Primetime Emmy nomination. Miranda debuted as a film director with Tick, Tick...Boom!.

His television work includes recurring roles on The Electric Company (2009–2010) and His Dark Materials (2019–2022). Miranda hosted Saturday Night Live in 2016, & and had a guest role on Curb Your Enthusiasm in 2018; he was nominated twice for the Primetime Emmy. He has been politically active on behalf of Puerto Rico. Miranda met with politicians in 2016 to speak out in favour of debt relief for Puerto Rico & raised funds for rescue efforts and disaster relief after Hurricane Maria in 2017.