Mukerji was born in Bombay (present-day Mumbai) on 21 March 1978. Her father, Ram Mukherjee (born to the Mukherjee-Samarth family), was a former film director and one of the founders of Filmalaya Studios. Her mother, Krishna Mukherjee, is a former playback singer. Her elder brother, Raja Mukherjee, is a film producer and director. Her maternal aunt, Debashree Roy, is a Bengali film actress and her paternal second cousin, Kajol, is a Hindi film actress and her contemporary. Another paternal second cousin, Ayan Mukerji, is a scriptwriter and film director. Despite her parents and most of her relatives being members of the Indian film industry, Mukerji was uninterested in pursuing a career in film. She said, "There were already too many actresses at home and I wanted to be someone different".

Mukerji prefers not to publicise her personal life. She limits her interactions with the media and is sometimes labelled a recluse; she said in a 2011 interview, "Today actors have become more open with the media. But this has posed a problem for actors like me because if I don't do that, then I end up being called reclusive. So now I have changed myself and am easily approachable." Mukerji has collaborated frequently and maintained a close friendship with actors Shah Rukh Khan and Aamir Khan, and filmmaker Karan Johar. She does not have any social media accounts, as she prefers to keep a low profile.

The nature of Mukerji's relationship with filmmaker Aditya Chopra was the topic of fervent tabloid reporting in India, though she refused to publicly talk about it. According to media reports, she and Chopra started dating soon after his divorce. "He was just out of his divorce and I think he was in no mind to see someone," Rani had told in an interview. On 21 April 2014, she married Chopra at a private Bengali ceremony in Italy. The following year, she gave birth to their daughter Adira. She has said that "the time spent being a mother is the happiest period of my life". Mukerji has said that she believes in maintaining a work-life balance after motherhood, adding that "it is extremely important for to have a career and use her time constructively". In 2023, she revealed that she had a miscarriage in 2020, five months into her second pregnancy.

Mukerji has featured in listings of the most attractive Indian celebrities, and was one of the highest-paid actresses in Bollywood. Filmfare featured her in their "Ten Most Powerful People in Bollywood" list for two consecutive years (2005–2006). Mukerji featured in Box Office India's "Top Bollywood Actresses" list for six years and ranked first for two consecutive years (2005–2006) and ranked 3rd in its "All Time Top Actress" list. In Rediff.com's annual listing of "Best Bollywood Actresses", she topped the list for three consecutive years (2004–2006). She was further placed 2nd in 2003, 5th in 2007, 10th in 2012, 7th in 2014, 10th in 2018 and 5th in 2023. She was also placed in Rediff.com's other listing - "Powerlist: Top Bollywood Actresses", "Bollywood's Best Actresses of all time", "Top 10 Actresses of 2000–2010" and "Best Dressed Woman". Filmfare further placed her in their "Top Ten Actresses" list from 2003 to 2006.