The mistake on this route is almost always the same: flying Lima to Cusco on day two and spending the next three days with a headache in a hostel at 3,400m. Everything that follows is arranged around not doing that.
Three weeks, overland where it matters, ending at the salt flats. Dry season, May to September, is the assumption throughout.
Days 1–3: Lima
Sea level, which is the point. Two full days here lets jet lag clear before you go anywhere high.
Barranco and Miraflores to stay. The Larco Museum for a pre-Columbian collection that reframes everything you will see later. Huaca Pucllana, an adobe pyramid in the middle of the modern city.
Lima is one of the best eating cities in the Americas and this is where to spend money on it — ceviche at lunchtime, which is when it is eaten, and the cebicherías rather than the tasting menus if the budget is finite.
Days 4–7: Arequipa and Colca
Fly to Arequipa (2,335m). A white volcanic-stone colonial city under three volcanoes, and — importantly — a moderate altitude to spend three nights at before going higher. This is the acclimatisation step almost every itinerary skips.
Santa Catalina Monastery is a walled city within the city and is the best single sight in southern Peru.
Colca Canyon, two days, with condors at the Cruz del Cóndor viewpoint in the morning and a night in the valley. The pass on the way crosses 4,900m, which is a useful high-sleep-low exposure.
Days 8–12: Cusco and the Sacred Valley
Bus or fly to Cusco (3,400m), but do not sleep there first. Go straight down to the Sacred Valley — Ollantaytambo (2,790m) or Urubamba — for two nights. It is lower, prettier and quieter, and it is the correct order.
Ollantaytambo’s terraces and the still-inhabited Inca street grid. Maras salt pans and Moray’s circular terraces.
Machu Picchu: train from Ollantaytambo, one night in Aguas Calientes, first entry the next morning. Buy the right circuit — read the destination page before booking, because the circuit choice is where people go wrong.
Then Cusco itself, two nights, by which point 3,400m is unremarkable. Qorikancha, the Inca stonework in the streets, San Pedro market, and the ruins above the city.
If you are walking the Inca Trail, it replaces four of these days and must be booked around six months ahead.
Days 13–15: Lake Titicaca
Bus Cusco to Puno (3,810m), ten hours, and the tourist buses that stop at Raqchi, Andahuaylillas and the La Raya pass are worth the small extra over the direct service.
Uros floating islands are a half-day and are frankly a performance; Amantaní or Taquile with a homestay is the version worth doing, and the two nights on the lake are many people’s favourite part of the trip.
Cross to Copacabana, Bolivia — a straightforward land border — and Isla del Sol for a night if you have it.
Days 16–18: La Paz
Bus to La Paz (3,600m), arriving over the rim of the bowl the city sits in, which is one of the great arrivals anywhere.
The teleférico — an urban cable car network that is also the best-value city tour in South America. The Witches’ Market. Valle de la Luna. Tiwanaku, an hour away, which predates the Inca by a thousand years.
Death Road mountain biking, if that appeals, is a full day and the operator you choose genuinely matters.
Days 19–21: Uyuni
Overnight bus or a flight to Uyuni, then the three-day 4x4 tour across the salt flat and the southern altiplano lagoons, finishing either back in Uyuni or at the Chilean border for San Pedro de Atacama.
Note the tour reaches 4,850m on the final morning. By this point in the itinerary you are thoroughly acclimatised, which is the entire argument for this ordering.
Choose the operator carefully. See the Uyuni page — this is the one booking on the trip where the cheapest option carries real risk.
Variations
Wet season (December–March) gives you the mirror on the salt flat and takes away the Inca Trail (closed in February) and reliable Machu Picchu views.
If you have four weeks: add the Amazon from Puerto Maldonado or Rurrenabaque, or Huaraz and the Cordillera Blanca, which is the best trekking in Peru and is skipped by almost everyone.
If you have two: cut Arequipa and Colca, fly Lima–Cusco, and accept two slow days in the Sacred Valley.
Practical
Altitude governs everything. The Andes page covers it properly.
Buses in Peru and Bolivia range from excellent to alarming. Pay for the premium operators on long overnight routes.
Cash — bolivianos in Bolivia especially — is necessary outside cities.
Two spare days somewhere in the middle. Bus routes get blocked by protests in both countries with little notice, and it is the single most common way this itinerary breaks.