It's been done professionally: see the novel Fatherland.
But just for the sake of argument, you'd need to remove FDR from the mix in the late 1930s/very early 1940s to minimize any interventionist tendencies/give the isolationists essentially a clear shot at the White House. Let's say for whatever reason, a cerebral hemorrhage occurs in January 1940 (I picked that date arbitrarily), yielding John Nance Garner as president.
Garner wouldn't be the choice by the convention (a presidential candidate from the south--in his case, Texas--was not viable at the time). Now you have a vacuum, especially in the internationalist camp, of leadership. That would allow Kennedy the opportunity to resign as ambassador to Great Britain and return, with his old FDR-based promises in hand. He's viewed as a more-or-less logical successor to FDR.
The Democrats' convention is a mad scramble, with several candidates (e.g., McNutt, Garner, Farley, Kennedy) all in the running. Kennedy may carry the day based on spraying around considerable amounts of his own money and strong appeals to urban Catholic voters/urban ethnic voters (I could see the Boston, Chicago, northern NJ, and Tammany Hall machines all lining up behind Kennedy). As a nod toward party unity, he names Burton Wheeler of Montana as his running mate.
The GOP convention in Philadelphia is equally up for grabs, with the isolationists (Taft, Vandenberg) apparently holding the upper hand over Willkie (and there's Herbert Hoover in the wings, hoping to be named in the event of a deadlock). I'll assume that the amateurs in the GOP still carry the day, naming Willkie as the candidate with McNary as his running mate as in OTL.
Now what we have is a role reversal on the national level, leading to mass crossing of party lines and ticket splitting. Isolationist Republicans, especially in the midwest, swallow hard and vote for Kennedy at the top of the ticket while returning their own kind to the House and Senate. At the same time, interventionist Democrats grit their teeth and vote for Willkie, while sending Democrats to Congress. But it's the dead rising to vote in New York, Boston, Chicago, and northern New Jersey (the Crump machine in Memphis is an exception) that carry the day for Kennedy (the GOP machine in Philadelphia isn't enough to balance those others) in a narrow victory.
What you now have in early 1941 is a solid isolationist in the White House who can reach across party lines. I could see Kennedy appointing Charles Lindbergh to some sort of post (possibly ambassador to Germany?), as well as dealing with Henry Ford (a known anti-Semite; possibly Secretary of Commerce?) and Gerald Nye (the Senate leader of America First). There won't be involvement with the war in Europe, although a naval war with Japan is not out of the question by any stretch.