Popocatépetl, one of the most hazardous volcanoes worldwide, poses significant threats for nearby populations in central Mexico. Therefore, it is important to reconstruct its eruptive history, including estimates of lava-flow emplacement times and their rheological properties. These studies define possible future eruptive scenarios and are necessary to mitigate the risk. Stratigraphic studies of the cal 350–50 B.C. Lorenzo Plinian pumice sequence indicate that effusive activity (Nealtican lava-flow field) occurred shortly after explosive activity, reflecting drastic changes in the eruptive dynamics. It was likely due to the efficient degassing of the magma during the Plinian phase and a decrease of magma ascent and decompression rates. Magma mixing, fractional crystallization, and a minor crust assimilation are the processes controlling the differentiation of the Nealtican lavas. We used lava chemical and mineralogical composition to estimate lava-flow viscosities, and used high-resolution elevation data to estimate emplacement times. Results indicate that lava viscosities of andesites and dacites ranged from 109 to 1012 Pa·s and emplacement durations were between ~1 and ~29 years, depending on the flow unit and morphological method employed. Considering the entire volume of emitted lava (4.2 km3) and a mean output rate of ~1 m3/s to ~15 m3/s, we estimated that the effusive phase that produced the Nealtican lava-flow field may have lasted ~35 years. This eruption had a considerable impact on pre-Hispanic settlements around the volcano, whose population exodus and relocation probably contributed to the rise of important cities in central Mexico, such as Teotihuacán and Cholula.