Allowing slavery when the Constitution was written. Then we could have avoided nearly ALL of the shit that followed. No Civil War, no KKK, no Jim Crow South, less gun control, no democratic party, no great society, no affirmative action, no gay-ass "wAr oF nOrThErN aGgReSsIoN" threads in ARFCOM.
(yeah, it enabled us to compromise enough with the southern states in order to ratify the Constitution. It was probably worth it, we are still the greatest, most free nation on earth.)
But in addition to all that's been mentioned so far, I am going to add COINTELPRO. The MKUltra drum gets beaten in ARFCOM all the time, and it pales in comparison to the widespread nature of COINTELPRO, where the government attempted to disrupt political and social organizations, using illegal behavior, up to and including murder.
Kinda like what's going on right now, come to think of it.