Such attitudes are also expected in architectural works, where the multiple influences of Bramante, Raphael, Antonio da Sangallo the younger and Baldassare Peruzzi can be seen, perhaps expressed a little rigidly, but also with a considerable capacity for the renewal of the architectural language of Ferrara of the time, which was otherwise ensnared in a sort of local dialect with strong Lombard and Venetian influences.
It is not known how Girolamo came to take up architecture without any technical training. What might be seen as fundamental in this respect is the example and the influence of the pictorial and architectural work of Baldassare Peruzzi, which the young Ferrarese painter studied in Bologna between 1525 and 1530, when he was working on the frescoes of the sacristy of San Michele in Bosco and on the altarpiece for San Salvatore.
The earliest major surviving architectural work, the palazzo Naselli Crispi in Ferrara, dates back to around 1530. The palazzo, praised as an example of fine architecture by Serlio in his treatise of 1537, appears to be a clear homage to Rome, both in its language and in its unusual and extremely precise construction technique.
Around 1536 Girolamo, who had returned definitively to Ferrara, was working on a steady basis for the Duke and certain members of his court. We should take note here of another work of the period, the altarpiece of Saint Jerome in the church of San Paolo in Ferrara. In the years between 1536 and 1548 Girolamo worked in a team with other painters including Dosso and Battista Dossi and Camillo Filippi, mainly on the grand decorative cycle which Ercole wanted for the palazzo di Copparo, Montagna di Sotto, the d'Este castle and in the Sala della Vigna at Belriguardo, the sole fragment of this great pictorial project which survives.
In 1540, Girolamo illustrated the anatomical treatise Musculorum humani corpori picturata dissectio for the doctor and university lecturer Giovanni Battista Canani. His careful cultivation of the court's humanists led to a collaboration between 1541 and 1548 with Giovanbattista Giraldi Cinthio for whom he designed the sets for the tragedy Orbecche, the pastoral Egle and the tragedy Antivalomeni.
On the death of François I of France on 31 March 1547, cardinal Ippolito II d'Este ordered a solemn funeral, held on 15 May of that year in Ferrara at the church of San Francesco where Girolamo and his father Tommaso had painted the frescoes many years earlier. The plans for the catafalque with statues, trophies and arms were commissioned from him by the cardinal, marking the beginning of a long and fruitful working relationship.
In August 1549, Girolamo settled in Rome, in the pay of the cardinal who in that very year signed a contract for the lease of the villa at Monte Giordano, while in 1550 another contract marks his acquisition of the villa and gardens of Montecavallo, better known as the Quirinale.
Of Girolamo's work for Ippolito II in Rome, it is known that as well as giving advice on purchases of ancient statuary and supervising the archaeological dig at the Villa Adriana he successfully prepared the antiquarium in the gardens of the villa at Montecavallo. The studies of the architecture of his contemporaries and the antiquities of Rome remain in the form of many signed drawings.
The fame which Girolamo achieved led him in 1550 to be one of the architects taken on by Pope Julius III for the work on the courtyard of the Belvedere. However, after just a year Girolamo resigned the commission, probably unable to cope with the ferocious rivalry between the artists working for the papacy. He thus returned to the service of cardinal Ippolito II, with whom he stayed until November 1553 when he returned to the court at Ferrara.
Here, on 1 February 1554, a fire devastated the d'Este castle. Girolamo, by then considered as the court's leading artist, carried out a radical reconstruction of the building, marking a definitive move away from its defensive role. With the mediaeval battlements replaced by marble balustrades and the towers topped with elegant roof terraces composed of niches and pilasters, the castle was completely transformed into a "civilian" building, from fortress to noble mansion.
The works on the castle occupied Girolamo up to 1556, when he received another commission from the Lateran Canons: the church of San Giovanni Battista in Ferrara; this was not, however, a matter of building a church from scratch, but of completing it. Unfortunately, Girolamo's ideas, still clearly visible from the plans, were unsatisfactorily executed by other hands, since the death of the architect a few days after the delivery of the drawings in August 1556 was to leave the project incomplete.