There are so many nightmare situations you can imagine.

A single missile loaded up with a highly contagious 100% fatal pathogen, use drones with infrared to pick off the remaining hermits.

Just drones. Self-replicating killing machines that know all the human tricks.

Neutrino bombs, a few million of them.

A horrible digging machine just digs and releases all that poisons stuff from under us. We all suffocate.

Sunblocker, apply for 30 years. The few remaining humans living in cannibalism around geothermal vents get nuked from orbit.

Giant space mirrors. Fry us.