A California native, Wiley studied art at Virginia Commonwealth University and worked for several Hollywood educational film studios before relocating to North Carolina in 1976 to work as an editorial cartoonist and staff artist for the Greensboro News & Record. Fenton (1982) was his first syndicated strip. In 1985, he was hired as an editorial cartoonist at the San Francisco Examiner.

In 1991, Wiley launched his popular Non Sequitur strip, eventually syndicated to 700 newspapers. In 1994, Miller pioneered the use of process color in comic strips, and developed a format in 1995 that allows one cartoon to be used in two different ways for both panel dimensions and strip dimensions.

Books by Miller include Dead Lawyers and Other Pleasant Thoughts (1993), The Non Sequitur Survival Guide for the Nineties (1995), Non Sequitur’s Beastly Things (1999, foreword by Jules Feiffer), The Legal Lampoon (2002), Why We’ll Never Understand Each Other (2003), Lucy and Danae: Something Silly This Way Comes (2005), Homer, the Reluctant Soul (2005) and Extraordinary Adventures Of Ordinary Basil (2006).

In 2004, Wiley Miller, his wife Victoria Coviello, and their four Jack Russell terriers moved from Santa Barbara, California, to Kennebunkport, Maine. He explained the relocation to Stephanie Bouchard of the Maine Sunday Telegram:

Part of the attraction for both of us is in a creative sense. Santa Barbara is beautiful. As far as year-round climate, it's perfect, but there's no real change. These dramatic changes really spark the creative nature because it's change. It gives you a fresh look at the world. It's invigorating. Santa Barbara is too nice; hard to get work done. We spent eight years in Iowa. Iowa is always overcast; it's awful. Here, in winter, we don't go out much so we get more work done.

When Bouchard asked him about the Maine setting in some of his strips, he responded:

I created a series of characters that came from our visits to Maine. Offshore Flo is patterned after the Maine Diner in Wells. I wanted to capture the essence of Maine people's genuineness - down-to-earth, good-natured people - and work in the accent. I heard from displaced New Englanders. I got E-mails from people who said how dead-on the accent was and how dead wrong. It's tricky working phonetically because you still have to be legible, finding the balance of how far to take it. It's set in Whatchacallit, Maine. I realized there had never been this setting in comics. I hate following. More fun blazing a new trail. Nobody's ever been to Maine in the comics.

Wiley was named Best Editorial Cartoonist by the California Newspaper Publishers Association in 1988 and won the Robert F. Kennedy Journalism Award for editorial cartooning in 1991. The National Cartoonists Society honored Non Sequitur with four awards in the first six years of publication, including their Newspaper Panel Cartoon Award for 1995, 1996 and 1998, and it was nominated for the same award in 1999 and 2002 and won their Newspaper Comic Strip Award for 1992.

Non Sequitur is the only comic strip to win its division during the first year of publication, and it is the only comic feature to win in two divisions, Best Comic Strip for 1992 and Best Newspaper Panel Cartoon for 1995, 1996 and 1998.

• 1988: California Newspaper Publishers Association
• 1991: Robert F. Kennedy Journalism Award, for editorial cartooning
• 1992: National Cartoonists Society, Newspaper Comic Strip Award
• 1995: National Cartoonists Society, Newspaper Panel Cartoon Award
• 1996: National Cartoonists Society, Newspaper Panel Cartoon Award
• 1998: National Cartoonists Society, Newspaper Panel Cartoon Award