After organizing exhibitions independently and for non-profits, Sean Horton opened his first gallery location, SUNDAY LES, on Eldridge Street on the Lower East Side in 2006. Under several names he has since realized more than 250 exhibitions and projects in a variety of interesting spaces and contexts. He was also responsible for sourcing over 100 artworks for the permanent collection of Soho House globally.

Horton presented the New York solo debuts of Elijah Burgher, Leidy Churchman, Corydon Cowansage, Lauren dela Roche, Keltie Ferris, Kate Groobey, Kirk Hayes, Paul Housley, Madjeen Isaac, Natasza Niedziółka, and Nyugen E. Smith, among others. He presented solo art fair booths by Saul Becker, Michael Berryhill, Leidy Churchman, Michael Cline, Keltie Ferris, Peter Gallo, Clare Grill, Kirk Hayes, Michael Jones McKean, Natasza Niedziółka, Asuka Ohsawa, Lauren dela Roche, Nyugen E. Smith, Orkideh Torabi, and Wallace Whitney.

Widely reviewed gallery exhibitions included those by Peter Gallo, Clare Grill, Michael Jones McKean, and Aaron Spangler. Horton also exhibited outsider artists Gayleen Aiken, David Byrd, Royal Robertson, and Miroslav Tichý, as well as artwork by notable indie musicians and filmmakers Martha Colburn, Joel Gibb, and G.B. Jones. The gallery hosted live musical performances by David Bazan, Kath Bloom, Geechee Dan, and L'Amour Bleu (with Stanley Love).

In Berlin, Horton hosted the European premiere of A.L. Steiner and A.K. Burns' film Community Action Center and presented group exhibitions including Joanne Greenbaum, Ella Kruglyanskaya, Orion Martin, Ryan McLaughlin, Anne Neukamp, and Daniel Rios Rodriguez, among others. Horton also offered artist residencies to Elijah Burgher, Gordon Hall, and Colin Self. 

In 2015 — 2016, Horton Gallery shared a 3500 square-foot exhibition space in Chelsea (alternating monthly) with ZieherSmith and collaborated on several art fair presentations as Zieher Smith & Horton.

In 2019 — 2020, Horton collaborated with curator and writer Joseph R. Wolin to present solo exhibitions by Leo Gabin and Lucia Hierro in Dallas. Artist Wallace Whitney organized Bushwick Rodeo including Katherine Bernhardt, Sadie Laska, and Rachel Eulena Williams, among others. Horton also presented a series of exhibitions on the Upper East Side of New York City including a solo exhibition by multi-disciplinary artist Kalup Linzy.

In 2022 — 2023, Horton operated from the 3rd Floor of a Manhattan Project era warehouse in the Chelsea neighborhood of New York City.

Horton regularly visits colleges and universities for student engagement and he has served on benefit committees for Brooklyn Academy of Music, New Museum, SRLP (Sylvia Rivera Law Project), and White Columns, among others. He was a member of the New Art Dealers Alliance (NADA) between 2007 – 2024.

In February of 2024, Horton accepted a position as Senior Director at Marc Straus Gallery on the Lower East Side of New York City.