Frank Lautenberg beating Millicent Fenwick in NJ in 1982 was a big upset I believe.
It was in the sense that Millicent Fenwick was considered unbeatable at the start of the campaign. As things went on, Lautenberg continued to flood the race with his own cash and negative ads. Fenwick refused to take PAC money, and was ultimately defeated because of it.
It's one of the saddest upsets in American politics, because Fenwick would have been an absolutely legendary senator. Lautenberg certainly isn't.
Fenwick was already quite old anyways so I doubt she would have lasted more than a term.
