Mignano began his career in the music industry at Atlantic Records before transitioning into tech, first at photo-sharing platform Aviary and then Adobe.^[6] In 2016, after struggling to produce podcasts on his own, he started Anchor to make it easier for aspiring creators to broadcast audio with co-founder, Nir Zicherman.^[7] The pair received financial backing from a variety of venture capitalists, including Accel, Google's venture arm GV, and the co-founders' former boss from Adobe, Scott Belsky.^[8]

In February 2019, Anchor was acquired by Spotify^[9] for more than $150M^[10] and Mignano became responsible for overseeing the Swedish audio streaming company podcast tech business, as well as their expansion into video and live audio.^[11] Under Mignano's leadership, Anchor has grown to power more than 75% of all podcasts.^[12] In 2022, after announcing he'd be leaving Spotify to focus on early stage tech investing,^[13] Mignano introduced a new feature enabling users to create, edit, and share podcasts directly in the Spotify app.^[14]

In 2022, it was announced that Mignano would be joining the Silicon Valley venture capital firm, Lightspeed.^[15]

In 2019, Mignano was featured as one of the main keynote speakers at the South by Southwest festival in Austin, TX.^[16]