If your trip is built around Cartagena's walled city and the Caribbean coast, adding Guatapé means flying inland to Medellín — a real detour, not a quick side trip. The question worth answering honestly isn't how to fit it in, but whether it's worth fitting in at all given what it costs you in time and money.
What the detour actually costs
A round-trip flight from Cartagena to Medellín runs roughly 1 hour each way, and realistically you'll want at least 2 full days in Medellín to make the flights worthwhile — one for the city, one for the Guatapé day trip. That's 2–3 days pulled from your coastal time, plus the flight cost and airport time on both ends.
What you get in return
Guatapé and Cartagena are two of the most visually distinct experiences Colombia offers — Cartagena's Spanish colonial walled city and Caribbean humidity versus Guatapé's mountain lake and rock climb. If your goal is to see Colombia's range rather than just its coast, this contrast is exactly what makes a Colombia trip feel complete rather than one-dimensional.
When it's not worth it
If your total trip is under 7 days, the detour usually isn't worth it — you'll spend a disproportionate share of a short trip on flights and transfers rather than experiencing either place properly. In that case, stay coastal and save Guatapé for a future trip built around Medellín.
When it clearly is
For trips of 10+ days, or for travelers who specifically want both a Caribbean beach experience and an Andean/mountain experience in one visit, the Medellín detour (Guatapé included) is consistently rated as one of the best decisions travelers make in their Colombia planning.