Shapiro was born in New Jersey. Spending his early years in New York City and New Jersey, Shapiro started his career in the early 1980s as a Comedian at Catch A Rising Star on Broadway. Besides performing regularly on stage, throughout the 1990s he acted and starred in numerous films by Louis CK, including Tomorrow Night. Additionally, he portrayed the re-occurring character "Angry Poet" in Late Night with Conan O'Brien. In 1998, Shapiro released his first comedy-CD called Unconditional Love, which Billboard called "hard-edged and uncompromising".

In the 2000s, Shapiro's career continues in multiple fields. He is performing stand-up comedy nationally and internationally, debuting a one-man show in 2007 in the Edinburgh Festival, and touring Australia in 2009. He had his first video game appearance in 2008, portraying the character Mason Waylon on the radio station PLR in Grand Theft Auto IV - a guest on a talk show who eventually drills holes in the heads of the two other guests.

Shapiro's first book Unfiltered, containing over 200 previously unreleased writings, was released in 2012 along with his second CD, Catalyst for Change.

In 2013, Rick Shapiro was diagnosed with Parkinson's disease. As of August 2014, he is practically symptom-free and is productive.

In 2014-15, Shapiro appeared in the role of Marc Maron's eccentric neighbor, Bernie, in the IFC comedy series Maron.