Returning from Madrefavat, Solyman commenced a heavy fire from his ships against the sea bulwark in which Francisco de Gouvea commanded, but was so well answered both from that work and the tower of St Thomas, that one of his gallies was sunk and most of her men drowned. The greatest harm suffered at this time by the Portuguese was from the bursting of some of their own cannon, by which several men were killed. Two brothers only were slain by the fire of the Turks. Zofar now so furiously battered the bulwark in which Pacheco commanded, that it became altogether indefensible, on which seven hundred janizaries assaulted it and set up their colours on its ruined walls; but the Portuguese rallied and dislodged them, killing an hundred and fifty of the enemy. The assault of this bulwark was continued a whole day, and at night the enemy were forced to retreat with much loss. Next day Pacheco deeming it impossible to resist, surrendered upon promise of life and liberty to himself and his men. Solyman did not perform the latter stipulation, but he granted their lives for the present and clothed them in Turkish habits. By one of these prisoners, Solyman sent a summons to Sylveira to surrender, but the proposal was treated with contempt. Solyman now planted his artillery against the fort, having among other cannon nine pieces of vast size which carried balls of ninety pounds weight. His artillery in all exceeded 130 pieces of different sizes, and his batteries were continually guarded by 2000 Turks. This formidable train began to play against the castle on the 4th of October 1538, and continued without cessation for twenty days, doing great injury to the defences of the fort, which could hardly do any injury in return to the besiegers, neither could the garrison repair sufficiently the most dangerous breaches, though they used every possible exertion for that purpose. On the sixth day after the commencement of this violent cannonade, perceiving that the bulwark commanded by Caspar de Sousa was much damaged, the Turks endeavoured to carry it by assault, but were repulsed with much slaughter, two only of the defenders being slain. Every day there were assaults by the besiegers or sallies by the garrison. In one of these Gonzalo Falcam lost his head; and Juan de Fonseca being disabled by a severe wound of his right arm continued to wield his lance with his left as if he had received no hurt. A youth of only nineteen years old, named Joam Gallego, pursued a Moor into the sea and slew him, and afterwards walked back deliberately to the fort through showers of balls and bullets. Many singular acts of valour were performed during this memorable siege.

At length many brave officers and men of the besiegers were slain, powder began to wax short and provisions shorter. The relief expected from Non Garcia Noronha, now come out as viceroy of India, was long in making its appearance. The remaining garrison was much weakened by a swelling in their gums, accompanied by their teeth becoming so loose that they were unable to eat what little food remained in the stores. Yet the brave garrison continued to fight in defence of their post, as if even misery and famine were unable to conquer them. Even the women in the fort exerted themselves like heroines. Donna Isabella de Vega, the wife of Manuel de Vasconcelles, had been urged by her husband to go to her father Francisco Ferram at Goa, lest the fort might be taken and she might fall into the hands of the Turks; but she refused to leave him. During the distress of the garrison, as many of the men were obliged to work in repairing the works, this bold-spirited lady called together all the women who were in the fort, and exhorted them to undertake this labour, as by that means all the men would be enabled to stand to their arms. The women consented to this proposal, and continued for the remainder of the siege to perform this duty. She was even outdone by Ann Fernandez, the wife of a physician, who used to visit the most dangerous posts by night, and even appeared at the assault to encourage the soldiers. Her son happening to be slain in one of the attacks, she immediately drew away his body, and returned to the place of danger, and when the fight ended she went and buried her son.

Perceiving that the Turks were undermining the bulwark which he commanded, Gasper de Sousa made a sally with seventy men to prevent that work and made a great slaughter of the enemy. When retreating he missed two of his men and returned to rescue them; but being surrounded by the enemy they cut the tendons of his hams, after which he fought upon his knees till he was overpowered and slain. The mine was countermined; but the continual labour to which the besieged were subjected became insupportable, and they were utterly unable to repair the many breaches in their works. At this conjuncture, four vessels arrived from the viceroy Don Garcia, and landed only a reinforcement of twenty men. Solyman was much concerned at this relief though small, and was astonished the fort should hold out against so many assaults, more especially as Zofar had assured him he might carry it in two. At the beginning of the siege the garrison consisted of six hundred men, many of whom were slain and several of the cannon belonging to the fort had burst; yet Solyman began to lose confidence, and looked anxiously to the sea, fearful of the Portuguese fleet which he had learnt was coming against him. This induced him to press the siege more vigorously, especially against the sea bulwark where Antonio de Sousa commanded, which was furiously attacked by fifty barks, two of which were sunk by the Portuguese cannon. The Turks made several attempts to scale this bulwark, in all of which they were repulsed with great slaughter, yet returned repeatedly to the charge with similar bad fortune. Sousa sent off his wounded men from the rampart to have their wounds dressed. Among these was a person named Fernando Ponteado, who waiting his turn heard the noise of a fresh assault, and forgetting the dressing ran immediately to his post where he received a fresh wound. Going back to get dressed, a third assault recalled him before the surgeon had time to attend to his wants, and he was a third time wounded, and at length returned to get all his three wounds dressed at once.

By this time, out of the original garrison of 600 men, only 250 remained that were able to stand to their arms. Solyman was almost in despair of success, yet resolved to make a desperate effort to carry the place. In hopes of putting Sylveira off his guard, and to take the place by surprise, he sent twelve of his gallies to sea, as if he meant to raise the siege; but Sylveira was not to be lulled into security, and continued to exert the utmost vigilance to provide against every danger. One night some noise was heard at the foot of the sea-wall of the castle, where it appeared that the enemy were applying great numbers of scaling ladders. Every effort was made to oppose them during the darkness of the night, and when morning broke, the place was seen beset all round by at least 14,000 men. The cannon of the fort was immediately directed against the assailants, and the garrison mounted the walls in every part, but chiefly near the governors house where the defences were weakest, but where Sylveira had placed such people as he could most rely upon. Being repulsed from thence with great slaughter, the enemy made an attempt on an adjoining bulwark, where Gouvea commanded, and poured in prodigious showers of bullets and arrows. Fourteen gallies came up against this bulwark, which they battered with their cannon; but Gouvea obliged them to draw off, having sunk two of the gallies and killed many of their crews. At length 200 Turks forced their way into the bulwark and planted their colours on its rampart. Scarcely thirty Portuguese remained to oppose them, yet they charged the enemy with great fury, who were so thick that every shot told, and they were driven out with much loss. Fresh men succeeded and regained the bulwark, on which they planted four standards. Many Portuguese who were wounded and burnt by the fireworks of the enemy ran and dipped themselves in jars of salt water, where seeking ease they perished in dreadful torment.