Centro Histórico: the base for a first visit
The historic centre is a compact grid of colonial streets between the Zócalo and the Barrio del Artista, and almost everything you come to Puebla for sits within a fifteen-minute walk: the Rosary Chapel in Santo Domingo, the Biblioteca Palafoxiana, the Amparo Museum on 2 Sur and the cathedral on the south side of the plaza. Hotels range from backpacker hostels off Avenida Juárez to restored casonas with courtyards around 5 Oriente and 3 Norte. Budget rooms cluster near the Mercado Victoria end; mid-range and upscale properties sit closer to the Zócalo and the Convention Centre on Avenida 5 de Mayo.
The trade-off is noise. Traffic on 5 de Mayo and Reforma runs late, and festival weekends, especially around 5 May and the December fair, fill the area and push rates up. Rooms set back from the street around a courtyard are worth asking for. If you plan to spend two or three nights walking, eating and museum-going, this is the area I would book, and I would book it early for spring and autumn weekends, which are the driest and most comfortable months.
La Paz and the Zona Esmeralda: quieter, still central
La Paz begins at the Paseo Bravo, about twelve minutes on foot south-west of the Zócalo, and runs towards Avenida Juárez. It is a residential and university-adjacent district with cafés, bakeries and a strong evening food scene along Avenida Juárez and Calle 11 Sur. Hotels here are mostly mid-range and business-oriented, with a handful of small design properties, and rates sit a notch below the centro for comparable quality. The streets are wider and calmer at night, and parking is easier if you are driving in from Mexico City on the Atlixco highway.
The Zona Esmeralda, further west along the Atlixco road, is a modern business and shopping corridor with chain hotels, large car parks and quick access to the ring road. It suits an overnight stop between Mexico City and Oaxaca, or anyone visiting the Volkswagen plant or the exhibition halls, but it has little of the city's character to walk to. For a leisure trip I would skip it unless I had a car and an early start the next day.
Cholula: the village base with the pyramid
Cholula sits about twelve kilometres west of central Puebla, roughly twenty-five to forty minutes by car or taxi depending on traffic on the Recta a Cholula, and it feels like a different town. The pyramid and the Nuestra Señora de los Remedios sanctuary on top dominate the centre, with the Zócalo of San Pedro Cholula and the portales of San Andrés Cholula a few minutes apart. Hotels are small, many in converted houses, and the area attracts travellers who want markets, mezcal bars and the university atmosphere around the Universidad de las Américas.
Cholula is the better base if your trip is long, if you are travelling with someone who wants quieter nights, or if you plan to use Puebla as a hub for Atlixco, Tonantzintla and the volcano foothills. The drawback is dependence on taxis or a car for Puebla's museums and restaurants. I would book two nights here and two in the centro rather than trying to do it all from one address. Weekend nights around the Zócalo are lively and can be loud; rooms on side streets are the practical choice.
Practical choices: timing, transport and what to skip
Puebla's dry season runs roughly November to April, with the clearest skies and the coolest nights, and the rainy afternoons arrive from May to October, usually concentrated in the late afternoon. Rates peak around Easter, the 5 May commemorations and the December–January holidays. The city sits at about 2,100 metres, so the first day is better spent slowly. If you are coming from Mexico City, the Estrella Roja and ADO buses from TAPO take around two hours to the CAPU terminal, from which a taxi to the centro costs a modest flat fare.
Skip the airport-area hotels unless you have a dawn flight; the Puebla airport is well east of town and there is little around it. Skip the Zona Esmeralda for a leisure stay, and skip trying to see Cholula, Africam Safari and the centro in a single day. For a first visit of three nights, I would book the centro. For a week, split it between the centro and Cholula, and use La Paz as a fallback if the centro is full during a festival weekend.