Rent a car at the airport and drive 5 hours to Lefkada. It’s a pretty drive on good roads and a bridge from the mainland connects to Lefkada. You can also get to Lefkada another way and rent a car in Lefkada.
At the Athens Venizelos Airport take a taxi to the KTEL bus station and catch a bus to Lefkada. The ticket is approximately 30 Euro and the air conditioned trip takes about 5 1/2 hours. These buses run three times a day.
You can sometimes take a short flight to Preveza on Aegean Air or Olympic Airways. Preveza is a mainland Greece town near Lefkada. From Preveza it’s a 30-minute cab ride to Lefkada. (Verify these still run)
British Air flies from London to Corfu, an island neighbor of Lefkada. From Corfu you would travel to the mainland and then drive a couple of hours to Lefkada.