- Zach Braff - Self
- Desiigner - Self
- Tracy Mann - Herself - Panelist
- Sara Benincasa - Herself - Panelist
- Martin Starr - Doug the Caveman
- Lauren Ash - Kale
- Jeff Dye - Eggplant
- Andi Osho - Bread
- Heather McDonald - Beef
- Aubrey Anderson-Emmons - The Director
- Solomon Georgio - Himself - Panelist
- Todd Barry - Vanilla (voice)
- Sandra Bernhard - Mint Choc Chip (voice)
- Matt Lucas - Salted Caramel (voice)
- Mario Cantone - Strawberry (voice)
- Margaret Cho - Pistachio (voice)
- Cameron Esposito - Chocolate (voice)
- Neil deGrasse Tyson - Self - Voice of Coffee Maker
- Rachel Bloom - Martian
- Rachel Bloom - Herself - Special Guest
- Prof. Mark Jacobson - Self - Panelist
- Richard Martin - Self - Panelist
- Taryn O'Neill - Self - Panelist
- Steve Aoki - Self
- Cara Santa Maria - Self - Panelist
- Alton Brown - Himself
- Cece Pleasants - HPV
- Cece Pleasants - Self - Voice of Wilhelmina
- Randy Couture - Tardigrade
- Andy Rossi - Tardigrade Victim
- Moogega Cooper - Herself - Panelist
- Hakeem Muata Oluseyi - Himself - Panelist
- Wil Wheaton - Himself - Panelist
- Diedrich Bader - Smallpox
- Jim O'Heir - Rabies
- John O'Hurley - Influenza
- George Wendt - Polio
- Derek Muller - Self - Correspondent
- Hilarie Cash - Herself - Panelist
- Gustavo Sorola - Rooster Teeth
- Geoff Ramsey - Rooster Teeth
- Karlie Kloss Kushner - Self - Correspondent
- Tim Gunn - Himself
- Nazeem Hussain - Himself - Correspondent
- Joanna Hausmann - Self - Correspondent
- Emily Calandrelli - Herself - Correspondent
- Mike Drucker
Sandra Bernhard interpreta a Mint Choc Chip (voice) en la serie.
Wil Wheaton interpreta a Himself - Panelist en la serie.
Bill Nye interpreta a Self - Host en la serie.
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