Systrom was born in 1983 in Holliston, Massachusetts. He is the son of Diane (Pels), a marketing executive at Zipcar, who also worked at Monster and Swapit during the first dotcom bubble, and Douglas Systrom, Vice President in Human Resources at TJX Companies.

Systrom attended Stanford University and graduated in 2006 with a bachelor’s degree in management science and engineering. At Stanford, he was a member of the Sigma Nu fraternity. He spent the winter term of his third year in Florence, where he studied photography.

After leaving Google to join Nextstop, a location recommendation startup founded by ex-Googlers that was acquired by Facebook in 2010, Systrom thought of combining location check-ins and popular social games. He made the prototype of what later became Burbn and pitched it to Baseline Ventures and Andreessen Horowitz at a party. He came up with the idea while on a vacation in Mexico when his girlfriend was unwilling to post her photos because they did not look good enough when taken by the iPhone 4 camera. The solution to the problem was to use filters, effectively hiding the qualitative inferiority of the photographs. Subsequently, Systrom developed the X-Pro II filter that is still in use on Instagram today.

In 2010, Systrom co‑founded the photo-sharing and, later, video-sharing social networking service Instagram with Mike Krieger in San Francisco, California.

In April 2012, Instagram, along with 13 employees, was sold to Facebook for US$1 billion in cash and stock. According to multiple reports, the deal netted Systrom US$400 million based on his ownership stake in the business. One of the key contributions to the acquisition was that Mark Zuckerberg stated Facebook was “committed to building and growing Instagram independently”, allowing Systrom to continue to lead Instagram. Systrom stated in an interview with Bloomberg that the pros of becoming a part of Facebook were that “we got to pair up with a juggernaut of a company that understands how to grow, understands how to build a business, has one of the best, if not the best, management team in tech and we got to use them as our resource”.

Under Systrom’s leadership, Instagram developed key features like the Explore tab, filters, and video. Over time, Instagram rolled out features allowing users to upload and filter photographs and short videos, follow other users’ feeds, geotag images, name location, and comment on other users’ photographs and short videos. Instagram allowed the development of web profiles in 2012, connecting accounts to Facebook, Twitter, Tumblr, and Flickr in 2013, an Explore tab in mid-2012, and Video in June 2013. Instagram offered 19 photographic filters; Normal, 1977, Amaro, Branna, Earlybird, Hefe, Hudson, Inkwell, Kelvin, Lo-fi, Mayfair, Nashville, Rise, Sierra, Sutro, Toaster, Valencia, Willow, X-Pro II.

In an interview with Forbes, he stated that “Instagram is a new form of communication that’s an ideal fit with the always-with-you iPhone in today’s social media world. Instagram’s a social network built around photos, where people can quickly comment on or ‘like’ photos and share them on Twitter or Facebook.” Systrom identified Instagram as a media company, which explains the roll-out of video advertisement by big companies such as Disney, Activision, Lancome, Banana Republic and CW in late 2014.

In 2014, Systrom was listed in the Forbes 30 under 30 list under the Social/Mobile category.

Also in 2016, CNN quoted a study according to which Snapchat was the most important social network among teenagers aged 14 to 19, the first time in two years that Instagram did not feature at the top.

In 2016, the magazine ranked Systrom as a billionaire with an estimated net worth of US$1.1 billion. The fortune came about as a result of Facebook stocks rising more than 500%.

In February 2016, Systrom met with Pope Francis at the Vatican, where they discussed the power of images in uniting people “across borders, cultures and generations”.

On October 31, 2016, Systrom married Nicole Systrom (née Schuetz), founder and CEO of clean-energy investment firm Sutro Energy Group, in Napa, California. The two met at Stanford and were engaged in 2014.

In May 2017, Systrom planned to better integrate the use of videos into Instagram. He also stated that in a few years, the company might be getting involved in Virtual Reality products.

On September 24, 2018, it was announced that Systrom resigned from Instagram and would be leaving in few weeks.