Most of his cartoon display racism, sexism, islamophobia, anti-semitism, climate change denial, the White genocide conspiracy theory, and anti-vaccine advocacy. Ironically, Garrison once denounced Neo-nazis and the alt-right when he learned that one of his cartoon strips were being edited to display racist imagery. He even went so far as to sue Christopher Poole (also known as moot), the creator of the website 4chan, on which the strip was edited and posted. Unfortunately, he later began embracing the alt right edits within his strips, even going so far as promoting such messages in his later strips.
Garrison originally wanted to pursue a career in the fine arts, but later began working as a graphic artist at the daily newspaper San Angelo Standard-Times instead, where his first editorial cartoon was published in 1980.
Garrison worked for the daily newspaper until it switched to an online-only format. He only began making political cartoons in 2009 after the financial crisis of 2007–2008, which prompted him to resume drawing after a 20-year hiatus. In 2009, Garrison made cartoons criticizing the Federal Reserve.
In 2010, Garrison uploaded a cartoon to the Internet called "The March of Tyranny." depicting global elite bankers as the Eye of Providence kicking members of the public with its legs, corresponding to both the Democratic and Republican parties, while barking orders from the mainstream media. The cartoon was his first to go viral and has since been translated into multiple languages. Subsequently, an Internet troll on 4chan posted an edited version of the cartoon in which the Eye of Providence has been replaced by an anti-Semitic caricature of a Jewish man ("Happy Merchant" by A Wyatt Mann). Internet trolls later edited some of Garrison's other cartoons in a similar fashion, and he has since been called the "most trolled cartoonist in the world". Garrison is often linked to white supremacy and anti-Semitism, leading to his refuted inclusion on a list of alleged Ku Klux Klan members leaked by Anonymous.
In 2014, Garrison spent more than 100 hours trying to remove libel on the Internet, but said it was "like trying to sweep the tide out with a broom."
From the summer of 2015 to January 2016, Garrison relied solely on his Patreon supporters and his political cartoons for income.
His cartoons often lionize American conservative figures and politicians such as former President Donald Trump and Rand Paul, and demonize liberal, moderate, and Never Trump movement figures such as President Joe Biden and Hillary Clinton.
In November 2015, Garrison uploaded a cartoon called "Attack of the Cry Bullies", which depicts college students as giant babies, with one of them in a "safe space" playpen. Books on logic and reason are shown burning in a fire in the foreground. After an image of the cartoon posted on Facebook was mass reported, the image was removed and Garrison's Facebook account received a 24-hour ban.
In 2016, Garrison said "I do cartoons that are anti-political correctness, anti-social justice warrior, because really what political correctness is is [sic] fascism with manners".
In May 2016, a cartoon of Garrison's comparing Michelle Obama and Melania Trump drew national attention. The cartoon showed a "scowling, masculine and dowdy" Obama contrasted against a smiling and feminine Trump, with the caption "Make the first lady great again!"
In June 2016, Garrison uploaded a cartoon about the Brexit referendum called "Abandon Ship", which drew criticism from The Guardian for its portrayal of Muslims and was retweeted by British-Belizean businessman Lord Michael Ashcroft.
His online attacks on survivors of the 2018 Stoneman Douglas High School shooting have also drawn criticism.
As Garrison's cartoons became more widespread, they have been regularly edited online including by Advance New Zealand and critics of the Bharatiya Janata Party in India.
Aside from political cartoons, Garrison does Cubo-Futurist paintings. For several years, he was represented by Bigfork’s ARTfusion gallery, until Internet trolls began harassing the owners of the gallery.