The series depicts the tribulations of the title character Parker Lewis (played by Corin Nemec), a Santo Domingo High School student, for whom nothing is impossible.

[citation needed] Parker Lewis Can't Lose features the titular character as frequent narrator of episodes.

Alongside Parker, Jerry Steiner and Mikey Randall are main characters whose primary focus through the show is fitting in.

The surrealism was toned down in the series' final season, going as far as having Parker acknowledge this by breaking the fourth wall and 'canceling' one of the show's transitions.

On SWV's 1992 debut album It's About Time, there is a song called "Blak Puddin'" which includes the line "Parker Lewis can't Lose in Santa Domingo."

Hip-hop group Naughty by Nature refers to the Parker Lewis character in their 1992 hit "Hip Hop Hooray".

The 1992 House of Pain song, "Feel It" includes the line "I can't lose like Parker Lewis, I'm undefeated."