Prince Harry and Meghan even gave an update about their 17-month-old son Archie during the event, saying that they're embracing "all of the quality time" with the tot.
But the focus was on the state of our digital experience and how to combat the negative effects of social media.
WATCH: Harry and Meghan talk quality time with Archie
Meghan said: "It can feel really overwhelming to try to understand all the nuance of what happens online. It is all-encompassing and it affects us at a multi-faceted level. And so we started with professors and experts in the field, with defectors from some of the largest platforms, neurologists - people to really help us view it through a holistic approach.
"And in that there have been relationships, and now friendships, that we have formed with a lot of these people who have a shared goal of wanting to make this space healthier and better for all of us."
Harry added: "What is happening in the online world is affecting the world. It is not restricted to certain platforms or certain social media conversations or groups. This is a global crisis - a global crisis of hate, a global crisis of misinformation, and a global health crisis."
Harry and Meghan gave an update about their son Archie
The couple talked about how the internet affected critical issues such as racial justice, gender equity, climate change and mental health, as they discussed how to create a safer digital world as part of TIME100 Talks.
Kicking off the chat with Edward Felsenthal, TIME CEO and editor in chief, he asked Harry and Meghan how they've been coping during the pandemic.
The Duchess said that "everyone is grappling with a different version of the same thing" before adding: "We're just trying to embrace all of the quality time we get with our son right now and not miss a single moment of his growth and development."
Serena and Alexis at Harry and Meghan's wedding in 2018
Harry said that "the media's role is absolutely vital in everything that's going on" and there is an " now more than ever, overwhelming desire" for everybody to find truth.
Meghan said: "It was only in the past couple of years we both started to connect the dots… all the work I was doing on women's empowerment or young girls and their sense of self worth, and seeing what the online spaces were doing to that community."
Harry and Meghan's guests included Reddit and co-founder of 776, Alexis Ohanian – husband to the Duchess' best friend and tennis star Serena Williams.
Speaking to Alexis about the power of social media and the online world, Meghan said: "The good outweighs the bad" but that the "bad can be so loud."
The couple were also joined by the young hosts of the Teenager Therapy podcast – whom Harry and Meghan spoke with on a special episode to mark World Mental Health Day.
A stunning new portrait of the Sussexes was revealed ahead of their appearance. The stunning black and white shot was taken by photographer Matt Sayles and showed Meghan wearing one of her signature trouser suits, looking relaxed as she sits on a chair.
The photo shows the Duchess beams shyly, not looking directly at the camera, as she rests her arm on her husband Harry's leg. The Duke, who was also dressed in a casual suit, sits on the arm of the chair putting one arm around his wife as he smiles at the photographer.
During the unveiling of the 2020 TIME 100 in September, the Sussexes implored Americans to exercise their right to vote in the US election on 3 November.
Harry and Meghan with Tristan Harris and Dr. Safiya Umoja Noble
Credit: TIME/TIME100 Talks
Harry spoke about the restrictions he has faced as a member of the royal family, saying: "This election, I'm not going to be able to vote here in the US.
"But many of you may not know that I haven't been able to vote in the UK my entire life. As we approach this November it's vital that we reject hate speech, misinformation and online negativity."
Harry and Meghan have been settling into their new life in the US since stepping back from royal duties in March.
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