The series centers on FBI special agents Dana Scully (Gillian Anderson) and her new partner John Doggett (Robert Patrick)—following the alien abduction of her former partner, Fox Mulder (David Duchovny)—who work on cases linked to the paranormal, called X-Files.

In this episode, Scully takes time off to deal with the early stages of her pregnancy, and Doggett and Walter Skinner attempt to avert the mysterious murder spree of a religious cult leader who kills his victims in their sleep.

Eventually, the cult leader's essence of evil possesses Doggett, who is urged to murder Scully while he sleeps.

Spotnitz was inspired to write the episode after being intrigued by the mental image of a tube of toothpaste that, when opened, oozed blood.

The following day, Dana Scully (Gillian Anderson) calls John Doggett (Robert Patrick) to inform him about the case and says she will not be joining him, due to personal matters.

Leeds' body is found in his car, but his partner, Stedman, is missing, along with cult leader Anthony Tipet (Keith Szarabajka): the man with the third eye.

He tells them that Tipet used the hallucinogenic plant Tabernanthe iboga as an aid to bringing himself closer to God using a combination of Christian and Eastern religious practices called the via negativa, (Latin for 'negative way' - a term used traditionally to describe a certain system of religious thought and practice).

Tracing Tipet's earlier call leads Doggett and Skinner to Andre Bormanis (Grant Heslov), a drug dealer.

Returning to the warehouse where they found Bormanis, Skinner and Doggett meet Tipet, who is trying to take his own life by pushing his head through a table saw.

[3] The idea inspired Spotnitz to work it into an episode, but due to its strangeness, he was unable to think of any real-world scenarios in which this would happens.

Gillian Anderson's character Dana Scully would not be available, since the writing staff had decided before the episode was written that she would spend most of her time in the hospital.

In order to fill Anderson's void, two recurring groups of characters were brought in: Walter Skinner and The Lone Gunmen.

[5] In preparing the character's death scene, Tony Wharmby, the episode's director, spent a whole day shooting inserts of rats.

In order to fix this, animal trainers continuously released more rats until the middle part of the room was finally covered.

[14] Although cautioning that "Via Negativa" is not "some kind of lost classic" and that the story itself was not "all that impressive", he praised the atmosphere of the episode, describing it as "heavy, doom-laden, and frequently bizarre".

[16] They further stated that it had an "eerie, almost surreal quality sprinkled with pithy dialogue, comic relief and cryptic insights into key characters that left us wondering what sort of trouble might be around the bend".

[16] Paula Vitaris from Cinefantastique gave the episode a moderately positive review and awarded it two-and-a-half stars out of four.

[17] She noted that, "'Via Negativa' is short on plot but makes up for it by being long on atmosphere and mood, conjuring up a number of disgusting, eerie images".