The news, which came four days after he was hospitalized for the overdose, sent Twitter abuzz with words of sympathy from his fellow comedians.
"Belly-laugh hilarious, prolific, good & kind," Sarah Silverman said on her Twitter. "A thousand oys can't express."
Comedian Jim Norton also expressed his condolences, Tweeting "RIP buddy" alongside a picture of the two guys.
Giraldo graduated from Harvard Law School, but ditched his job as a lawyer to show off his comedic chops. He was a regular guest on The Howard Stern Show and Comedy Central's Roasts.
"Have you ever not been drunk?" he joked during a recent David Hasselhoff roast. "You used to have a car that started when you talked to it. Now you have a car that won't start when you blow into it."
Despite his penchant for insult-style humor, the comedian had a darker problem: He struggled with alcohol addiction, which he discussed on the Stern show in September 2005 when he revealed he had been sober – except for one set-back – for five months.
Comedy Central, his TV stomping grounds, released a statement Wednesday emphasizing his contribution to the industry: "The tragic news of Greg's passing hits us very, very hard," the statement read. "The comedy community lost a brother today. Our thoughts are with his family."