Guatapé and Villa de Leyva rarely compete for the same travelers because they sit on opposite sides of the country and anchor different cities — but people building a Bogotá-plus-Medellín itinerary often ask which colonial-adjacent stop is worth the detour.
Two completely different landscapes
Villa de Leyva sits in Boyacá, about 3 hours from Bogotá, in a high, dry, almost desert-like valley at over 2,100m. Its enormous cobblestone plaza — one of the largest in South America — is ringed by whitewashed colonial buildings that haven't changed much since the 1600s. It's a history and architecture destination: fossil museums (the region is famous for dinosaur and marine fossil finds), a terracotta desert nearby, and colonial churches.
Guatapé is the opposite: a 1970s-era reservoir town built after a hydroelectric dam flooded the original valley, with a modern painted-zócalo aesthetic and a rock to climb. It's a nature-and-lake destination near Medellín, not a colonial one.
Which city are you anchoring from?
This is really the deciding factor. If your trip centers on Bogotá, Villa de Leyva is the natural day-or-overnight trip — it's not remotely convenient from Medellín (8+ hours by road). If your trip centers on Medellín, Guatapé is the natural choice, and Villa de Leyva would require backtracking to Bogotá.
Climate note
Villa de Leyva is notably drier and cooler than Guatapé — expect strong midday sun, cold nights, and almost no rain most of the year, versus Guatapé's warm, humid, rain-prone climate typical of Antioquia.
Verdict
These aren't really either/or choices in practice — they're both worth visiting if your itinerary includes both Bogotá and Medellín, since each is the natural side trip from its respective base city.