Joe Manganiello reveals the 'brutal side effects' he battled from treatment for 'deadly mystery illness'

Joe Manganiello has shared more details about the debilitating 'deadly mystery illness' that afflicted him in recent years and led to a 'life-saving organ amputation.'

In an Instagram video posted on Wednesday, the 49-year-old Magic Mike actor revealed that the treatments he was prescribed for the illness, which he has not yet disclosed, had their own 'brutal side effects.'

He also clarified just how private he kept his illness, saying that he 'suffered in silence, battling a deadly mystery illness' while only sharing the details with a small group of people closest to him.

Manganiello – who split from his wife Sofía Vergara in 2023 –  battled crushing uncertainty, as he was left without answers about what set off his health issues despite seeing 'the best doctors in the world.'

'All their attempts to treat it with high-powered biological drugs only exacerbated my symptoms and then unlocked a host of brutal side effects that winded up plaguing me for years,' he continued.

The 49-year-old actor – who is now engaged to the model and actress Caitlin O'Connor – teased that he would reveal more about his mystery illness in his upcoming memoir, Bloodlines, which will be released on October 13.

The True Blood star went on to detail the effects of the aggressive treatments he turned to.

'And then in attempts to buy myself time, I underwent very serious operations and procedures that mutilated parts of my body,' Manganiello said, adding that the procedures left him 'so weak' that he sometimes was unable to 'stand up or walk.'

As a result of his illness – and the treatments, which sounded nearly as brutal – he was 'heavily medicated' for months and was afflicted with 'excruciating bouts of chronic pain.'

Manganiello went on to highlight the meaning of his upcoming memoir's title, Bloodlines, by revealing that, as a result of his illness, he spent a decade researching his family history to understand what had sidetracked his life.

'Maybe what happened to me wasn’t random,' he mused in his Instagram video. 'And that in order to heal, my mind, my body, my spirit all had to align and I needed to become open to some really radical and unorthodox techniques and ideas that lie beyond the boundaries of western medicine.'

He concluded by offering words of encouragement for other people who are currently struggling with overwhelming or unexplained illnesses.

'If you’re out there and you’re suffering, there’s hope,' he added. 

The update comes after Manganiello opened up for the first time about suffering from an autoimmune-related illness over seven years with the announcement of his upcoming memoir.

According to a press release, Manganiello writes about how he has been dealing with 'a cascade of autoimmune-related illnesses' which wreaked havoc on his skin, thyroid, eyes, lungs, and digestive system.

This sent him on a seven-year journey, which was 'plagued by chronic pain, a life-saving organ amputation, existential crisis, and a prolonged fight for survival that left doctors with few answers and no clear explanation.'

As he was frustrated with traditional medicine's inability to give him any answers, he found a rather unorthodox solution.

The synopsis explains that the star explored 'shamans, pagan rituals, ancient myths, long-lost family records and the rebirth of his own spirituality.'

On the journey, he looked into his own family genealogy, where he discovered ancestors who had survived the Armenian genocide, in addition to others who lived with chronic illness. 

In the upcoming book, Manganiello will explore his illness, inheritance, masculinity, faith, ambition, and identities that we all build.

The press release concludes: 'More than a memoir of medical crisis, it is a searching account of what happens when the life you have constructed can no longer contain the truth of what you carry.

'Deeply personal and emotionally expansive, Bloodlines considers how the past lives on in the body and in the stories we tell about strength, survival, and selfhood. 

'The result is both a page-turning, heart-pounding story for the ages and an essential meditation on inheritance, loss, and the work of living with what remains.'

Manganiello's memoir Bloodlines will hit bookshelves on October 13. 

Meanwhile, Manganiello and Two and a Half Men actress Caitlin O’Connor were first linked in September 2023 and made their relationship official in December.

The couple announced their engagement in October 2025, revealing Manganiello had actually popped the question months earlier in June.

He and Vergara split in July 2023 after seven years together.

They said in a statement posted on Instagram at the time: 'We have made the difficult decision to divorce. As two people that love and care for one another very much, we politely ask for respect for our privacy at this time as we navigate this new phase of our lives.'