Start with the 13:55 Lufthansa flight from Istanbul to Frankfurt, about 3h 10m. Transfer in Darmstadt central, then take the 20:15 FlixBus bus on to Frankfurt (15 min). Transfer in Frankfurt, then take the 21:00 (+1d) FlixBus bus on to Prague (7h 25m). You arrive in Prague around 04:25 (+1d). In total it's roughly EUR 166 over 19h 50m, 2 transfers.
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Opens Omio — enter your date to compare trains and buses for this route; the price is finalised at checkout.
Fly into Darmstadt central, then continue to Prague by bus (15 min) — routing via Darmstadt central keeps the trip simple. Flight (Lufthansa, 3h 10min) + Bus (FlixBus, 15min) via Darmstadt central + Bus (FlixBus, 7h 25min) via Frankfurt.