What does "let's go with that" mean here?
In this case, he's using a common sarcastic figure of speech meaning "although I disagree with your reasoning, it's an acceptable alternative to the truth."
Put simply, Howard knows that the reason they go home alone is not because they are "so smart, it's off-putting" but actually because of their lack of social tact and standing. The truth is so less appealing that Howard says "let's go with that [a lie]" for the sake of their own self-esteem.
A: I'm not fat, I'm big-boned
B: Sure, let's go with that