Ugly Betty is the story of Betty Suárez, a good-hearted girl from Queens, New York, brave but sorely lacking in fashion sense and aesthetic polish. Betty is suddenly thrust into a different world when she is hired as a personal assistant at Mode, a fashion magazine headquartered in Manhattan and part of the publishing empire of the wealthy Bradford Meade and his family.

The only friends that Betty trusts at Mode are seamstress Christina McKinney and accountant Henry Grubstick, to whom Betty is attracted; meanwhile, at home she relies on her father Ignacio Suarez, older sister Hilda and Hilda's son Justin. Daniel's family, includes his mother Claire Meade; and, after returning from a two-year disappearance, his transsexual and competitive sister Alexis Meade (formerly known as Alex), who has made a successful transition to being female.

Despite being hard working, smart, and productive, Betty’s dream has always been shadowed by the fact that she isn't as traditionally beautiful as her cover ready colleagues. But despite it all, she is determined to do whatever it takes to fulfil that ultimate dream. Betty Suarez has always had one goal in life: to make it into the publishing business.