Has an NFL game ever ended 21-3?
It has. 21-3 has been a NFL final 23 times in 18,234 games. The first was Green Bay Packers beat Staten Island Stapletons on November 27, 1932; the latest was Carolina Panthers beat Tampa Bay Buccaneers on October 23, 2022.
That makes 21-3 the 218th most common final score out of 1,095 that have ever occurred in NFL. One point away, 22-3 has happened 8 times and 21-4 has happened never.