Pisano began his career in his father Nicola Pisano's workshop and so thoroughly assimilated the ideas he found there that his early work is difficult to distinguish from that of his father. It was in the contract (1265) for the pulpit in the Siena cathedral that Pisano is first specifically mentioned as an assistant to his father. Since he was at that time not referred to as “magister,” or independent master craftsman, Pisano must still have been in his teens. At any rate, by September 1285 he had rejected his Pisan citizenship and had become a resident of Siena. Around this time he began his work on the design and sculptural ornamentation of the facade for the cathedral of Siena which became, in its lavishness and ordering, the model for virtually all future Gothic facade decoration in central Italy. Unlike French examples, in which figural ornament pulsates over the entire facade, Pisano's designs for the Siena facade offer a much more architectural approach to the problem. The lower story is simply decorated with colonnettes (small columns) and a restrained foliate pattern, which follows the vertical movement of the colonnettes. Aside from the carved lintels over the doors, figural sculpture begins at the level of the arches over the entrances with slightly larger than life-size figures of prophets and sibyls and continues throughout the rest of the facade. Although each figure inhabits a discrete niche, agitated, forward-bending poses cause them to converse across the vast space of the facade and soften the otherwise clearly stated architectonic lines that order the structure. Recent research has emphasized particularly close relationships in design between the sculpture of the Siena facade and French foliate patterns and figural reliefs, especially from the cathedral at Auxerre. Since there are no known documentary references to Giovanni Pisano between 1268 and 1278, the possibility of a trip through France during these years seems extremely likely.

Next to the Siena cathedral facade, Pisano's pulpit in Pistoia, completed in 1301, is his greatest achievement. The five narrative reliefs of this pulpit roughly parallel the subject matter of his father Nicola's Pisa pulpit 40 years earlier, as does the overall architectural format, but the style pushes the expressive qualities innate in Nicola's Pisa pulpit to a new level of intensity. In the “Annunciation,” the “Nativity,” and the “Annunciation to the Shepherds,” the extreme agitation that characterizes all the reliefs for the Pistoia pulpit pulsates throughout the panel. Figures, animals, drapery, and landscape features are wrenched into physically impossible configurations; light shatters over the broken surfaces and deeply cut relief; and each figure responds convulsively to the individual situations in which he acts as a participant. What is critical to the change in style from the first Pisa pulpit reliefs to the Pistoia reliefs is a preference for an overall agitated and deeply cut surface as opposed to the earlier more massive and monumental organization of forms.

Pisano never repeated the frenzy of forms that covers the Pistoia pulpit. Instead he returned to the more stately, classical spirit that had been at the heart of his father's earliest work. The reasons for this cannot be documented, but they most likely stem in part from Giovanni's experience with Giotto's monumental and heroic style which was already in the ascendancy by the time that the Pistoia pulpit was completed. Pisano, in fact, carved a marble Madonna and Child for the Arena Chapel in Padua at approximately the same time that Giotto painted his profoundly moving fresco cycle there (c. 1305). In addition, the quasi-imperial political movements established by Pope Boniface VIII at the turn of the 14th century may also have prompted him to return to more overtly classical quotations.

From 1302 to 1310 Pisano again worked in Pisa, this time for a pulpit for the cathedral. In this pulpit, now badly reconstructed after having been disassembled, the relief style is considerably more docile than that of the Pistoia reliefs. His last recorded work was a tomb sculpture for Margaret of Luxembourg in Genoa in 1311 (fragments now in the Palazzo Bianco). He was last recorded in Siena in 1314, and it is presumed that he died shortly thereafter. If, as is clear from his work in Siena, Pisano was Italy's only Gothic sculptor, it is also true that he never lost sight of the heritage of classical Rome that underlies all of the artistic thinking of central Italy.