Meg, 57, looked stylish in a black tuxedo for the event, which began the 10th annual Turner Classic Movies Film Festival on Thursday.
Billy, 71, went for a more relaxed look in a navy blue suit and trainers.
The movie was a surprise hit in 1989, making more than £70million.
Screen-writer Nora Ephron won a Bafta and received an Oscar nomination for her witty, razor-sharp script.
The film, set in New York, tackles the age-old debate about whether men and women can having a platonic relationship and follows the fortunes of Harry and Sally over 12 years.
Despite their differences they grow close and by the end they are head-over-heels in love.
Meg’s character also provided one of cinema’s most notorious scenes in the middle of a busy restaurant, prompting a diner’s iconic one-liner: “I’ll have what she’s having.”
Director Rob Reiner, 72, said: “When it comes to men and women there are basic truths that are universal and they do stand the test of time. So hopefully that’s why people still connect with it.”
Meg said her chemistry with Billy helped the film’s success.
She said: “It’s the kind of music Billy and I knew how to play together.”
But when asked if there would be a sequel, Billy said everyone was happy to leave the characters alone.
“We talked about that for years and years and years,” he said.
“And for those of us who believe in happily ever after, that’s where they are and that’s where they should be.”
Along with the late Nora Ephron, another star missed at the event was Carrie Fisher, who played Sally’s friend Marie. The 60-year-old Star Wars actress died of a heart attack in 2016.