Safran was born in Melbourne to Jewish parents. His maternal grandparents were Polish Jewish Bundists. Safran's mother, Gitl, was born in Uzbekistan as they were fleeing their home country for Australia. She died in 2003.

As of 2002 Safran had been a regular host of Melbourne community radio station 3RRR (Triple R) on its morning show "Breakfasters". Additionally, he co-hosted the weekly radio show Sunday Night Safran on national youth radio station Triple J with Father Bob Maguire. After a lengthy hiatus late 2008 due to a busy filming schedule, Sunday Night Safran returned to the airwaves on 12 July 2009. The program ended at the end of 2015.  The program was iconic because the co-hosts talked to each other for much longer than instructed to (one such incident involved Fr Bob and Safran looking up the word monstrance in a dictionary following a dispute) and referring to the audience as "Dear Listeners". By Safran's own admission, Maguire and he "only seem to talk about Scrabble and White Supremacists".  During the program's run, Safran and Maguire were able to get interviews from people such as religious scholar Reza Aslan, Julian Assange's mother Christine, The Exorcist star Linda Blair, philosopher and School of Life founder Alain de Botton, writer, retired prison doctor and psychiatrist Theodore Dalrymple, West Memphis Three Damien Echols, antitheist Christopher Hitchens, conspiracy theorist David Icke, former white supremacist skinhead Frank Meeink, pro-euthanasia doctor Philip Nitschke, The Act of Killing director Joshua Oppenheimer, journalist and writer Jon Ronson, true crime writer and Ted Bundy co-worker Ann Rule, the Lizardman Erik Sprague, African-American pro-Israel political activist and Zionist Chloe Valdary, Jewish activist against child sexual abuse Manny Waks, psychic Lisa Williams and John Safran's dad, Alex.

When did he become a radio presenter?
2002