The A-list pair brought a touch of star power to Leicester Square on Tuesday night as they walked the blue carpet.
They were joined by the film’s 14-year-old lead, Storm Reid, who wore a bright pink dress with crystal collar and brooch.
A Wrinkle in Time tells the story of Meg Murry (Reid) a young girl who sets of on a quest to find her father (Chris Pine) who disappeared after finding a new planet, accompanied by three astral travellers.
The travellers, called Mrs Whatsit, Mrs. Who and Mrs Which, are played by Witherspoon, Mindy Kaling and Winfrey, respectively.
Also appearing on the red carpet alongside the film’s stars, were director Ava DuVernay ad producer Jim Whitaker.
Ahead of the premiere, Winfrey and Kaling appeared on BBC chat show The One Show.
Winfrey used the opportunity to ask her co-star if she had leaked the news she was having a baby to the press.
"Did I [leak your pregnancy]? People keep saying to me that I did it. Did I do it?" she asked.
"Yes. This is what happened. I was showing, my pregnancy was showing. So people were assuming that I was pregnant. The news had leaked that I was pregnant but I hadn't confirmed it, mostly for vanity's sake," Kaling replied.
"I had told Reese and Oprah almost immediately because we were at a press event at Disney World, and overcome with emotions, and I wanted to tell them. So, I told them.
"I think [Oprah] said in an interview, 'I'm very excited for Mindy to have her baby' — thus confirming. What they did, is they tricked you. They said, 'You must be excited for Mindy and her baby', and you said you were."
Winfrey confirmed the story saying: "Did I know that was a trick question? To this minute, no."
A Wrinkle in Time arrives in cinemas in the UK on March 23.