Mo was also seen co-starring alongside Dwayne ‘The Rock’ Johnson in the DC Comics superhero film Black Adam. The film grossed over 393 million dollars globally where he was the scene stealing comedy relief to The Rock.

Amer has performed tours in over 27 countries on five continents, including Germany, Italy, Sicily, Japan, Korea and Bahrain, as well as with other Muslim comedians Preacher Moss and Azhar Usman in the Allah Made Me Funny comedy tour since 2006. Recently Mo has had two Netflix comedy specials: Mo Amer: The Vagabond and Mo Amer: Mohammed in Texas on November 30, 2021.

In 2018, Amer joined the cast of the Hulu show Ramy, starring Ramy Youssef, where he plays Ramy's cousin Mo, who owns and operates a diner, where many of the show's characters congregate. The third season of the show premiered in fall 2022.

Amer developed his first solo feature-length documentary-comedy special, working with long-time standup collaborator Azhar Usman, co-produced through their jointly owned production entity, Kalijaga Media LLC. On May 3, 2015, Amer recorded his one-hour special, Legally Homeless, at the Warner Theatre presented by Live Nation Comedy. He became the first Arab-American to star in his own nationally televised one-hour stand-up special. The show's title is derived from the fact that Amer has traveled to more than 20 countries without a passport, and straddled multiple cultures while growing up in the U.S. Legally Homeless includes appearances by Azhar Usman, Bassem Youssef, Hasan Minhaj, Ramy Youssef, and independent rapper Brother Ali.

In June 2013, Amer featured on an interfaith special, What's So Funny About Religion?, which was broadcast on the CBS Television Network.

As well as with Allah Made Me Funny, Amer has performed at sold-out shows worldwide, including Royal Albert Hall and Hammersmith Apollo, Acer Arena, Nelson Mandela Theatre , Shrine Auditorium, as well as the Malmö Arts Festival (Sweden), the Amman Stand-up Comedy Festival, and the World's Funniest Island Festival.

Amer is of Palestinian descent, and the youngest of six children. Amer's father worked as an engineer for the Kuwait Oil Company. In October 1990, at the age of nine, Amer, his sister, Haifa, his brother, and mother fled his birth country of Kuwait during the Gulf War. They emigrated to the United States and settled in Houston, Texas. Two years later in 1992, Amer's father, a telecom engineer, joined them in the United States. Amer attended school at Piney Point Elementary while his older brothers studied overseas. His brother Omar is a pilot; another brother, Amer (who later changed the family name to Najjar), has a PhD in biochemistry. In 1995, when Amer was 14 years old, his father died

After the death of his father, Amer started being truant and taking unsanctioned trips to Mexico with his friends. An English teacher made a deal with Amer that if he performed a monologue from William Shakespeare in front of her class, she would reinstate his grade before his truancy began and allow him to try comedy in front of the class every Friday. Amer graduated and focused on his passion. He then participated in and had leading roles in high school theatre, and started performing stand-up comedy by impersonating family members and developed it over a few years in the comedy club scene. Amer performed at Houston's comedy clubs as often as possible to refine his act while working a day job at a flag manufacturing company owned by a family friend.