Screenwriter Frank Darabont first met director Chuck Russell in 1981, while working as a production assistant on the film Hell Night. Before working together on The Blob, the two also collaborated on the script for A Nightmare on Elm Street 3: Dream Warriors.
Actor Del Close had been scheduled to direct a "mock opera" about Ronald Reagan at New York's Lincoln Center for the Performing Arts during the filming of The Blob; however, the production was cancelled and he was unexpectedly available to audition for The Blob.
Production began on January 11, with the cast and crew of approximately 150 staying at a Travelodge in Abbeville, Louisiana. Due to the large amount of night shooting, the cast often slept during the day. On their off days, they watched videos at the hotel and ate crawfish, a popular item of local cuisine.
Special effects in the film were handled by Tony Gardner. Gardner was originally supposed to provide only a few small effects, with special effects artist Lyle Conway originally being in charge of the effects. However, after personnel changes he ended up running a crew of 33, including artist Chet Zar and mechanical effects designer Bill Sturgeon. In creating the titular Blob creature, the special effects team used silk injected with Methacil, a food additive, creating what the team described as a "Blob Quilt". For the few minutes of screen time, near the end of the film, where Reverend Meeker has a scene with fresh burns and another with healed burns, actor Del Close required five-and-a-half hours of makeup preparation for fresh burns, and seven-and-a-half hours for healed burns.