Can a novel have two main characters, even if one character only appears once but has a significant impact on the story?

I would say no. Even if the character has “significant” impact, if the story doesn't dedicate primary screen time to them, they aren't a “main” character.

To me, a character is the protagonist when they are a significant contributor to the story's resolution.

From a storytelling standpoint does it make sense to follow a guy/gal who is irrelevant to the plot?

So, this becomes a question of semantics. Can a story have multiple “main” characters?

ABSOLUTELY.

However, in the scenario described, you have a protagonist and a peripheral character (like a mentor or something) who affects the protagonist and thus the story.