The most geographically dispersed Games in history will get underway in Italy's economic capital at 20:00 CET with a three-hour extravaganza.
Parts of the opening ceremony will also take place in three other sites spread across the Alps and the Dolomites. For the first time, the 2,900 athletes will parade in the venues closest to where they will compete, in a bid to minimise travel.
The ceremony is expected to draw a global audience of hundreds of millions, and creative director Marco Balich intends to pay tribute to Italian design and fashion, with a special nod to the designer Giorgio Armani, who died last year.
American singer Mariah Carey, Italian tenor Andrea Bocelli and Chinese pianist Lang Lang are to perform, while dozens of dignitaries will attend including US Vice President JD Vance and US Secretary of State Marco Rubio.
Vance met International Olympic Committee president Kirsty Coventry, who is overseeing her first Games since her election last year, at a dinner for heads of state on Thursday. The United States hosts the next Olympics, the 2028 Summer Games, in Los Angeles.
Balich has said the ceremony will offer "a unique platform to convey positive messages, not divisive ones" amid concerns that American officials and athletes will draw boos from the crowd given the current political climate. One of the most prominent US athletes, reigning Olympic snowboard champion Chloe Kim, took apparent aim at President Donald Trump's immigration crackdown as she arrived in Italy.
Kim said in an Instagram post she was proud to represent a country that is "strongest when it embraces diversity, dignity, and hope".
"My parents left South Korea in search of a better future for their family. They left behind everything they knew so that my sisters and I could have the chance to one day live the American dream," she added.
The Olympic flame reached Milan on Thursday but organisers have tried to keep the identity of the final two torchbearers for the opening ceremony under wraps. It has been reported that they will be Alberto Tomba in Milan and Deborah Compagnoni in Cortina, two of Italy's most decorated alpine skiers.
The torchbearers will simultaneously light two cauldrons inspired by Leonardo da Vinci's geometric knot patterns, one suspended under Milan's Arch of Peace, and the other in Piazza Dibona in Cortina.