The Australian actor and singer, 32, revealed the news to his Instagram follows.
Ruffo first battled the diseased between 2017 and 2019.
Alongside a photo with his girlfriend, Tahnee Sims, Ruffo wrote: “After an unexpected week of seizures and excruciating headaches it is with a heavy heart that I have to let you know I now have another huge battle ahead of me as my brain cancer has returned."
Ruffo said he "will dig deep and beat this s*** disease again".
The actor, who appeared as a contestant on X Factor Australia in 2011, joined Home and Away in 2013.
He played Chris Harrington until departing the soap in 2016.
In 2012, he won the Australian version of Dancing With The Stars.
His former Home and Away co-stars, including Georgie Parker and Lincoln Lewis, sent their well wishes to the actor.
In August, he shared an update on his health three years after first being diagnosed with brain cancer.
“Three years today since I received the most devastating news of my life," he wrote.
"Thankfully with all the help & support from everybody around me I’m still here today kicking cancers asse [sic],” he wrote.
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