In the first half of the 16th century plague was still prevalent in Spain. According to George C. Kohn, “One of the worst epidemics of the century, whose miseries were accompanied by severe drought and food shortage, started in 1505; by 1507, about 100,000 people had died in Andalusia alone. Andalusia was struck once again in 1646. For three years, plague haunted the entire region, causing perhaps as many as 200,000 deaths, especially in Málaga and Seville.”

A second insurrection, the Morisco Revolt (1568–1571), ensued in the Kingdom of Granada. It was crushed and the demographics of the kingdom of Granada was hammered, with the Morisco population decreasing in number by more than 100,000 including deaths, flights and deportations, contrasting with the less than 40,000 number of incoming settlers.

In 1810–12 Spanish troops strongly resisted the French occupation during the Peninsular War (part of the Napoleonic Wars).

Andalusia profited from the Spanish overseas empire, although much trade and finance eventually came to be controlled by other parts of Europe to where it was ultimately destined. In the 18th century, commerce from other parts of Spain began to displace Andalusian commerce when the Spanish government ended Andalusia’s trading monopoly with the colonies in the Americas. The loss of the empire in the 1820s hurt the economy of the region, particularly the cities that had benefited from the trade and ship building. The construction of railways in the latter part of the 19th century enabled Andalusia to better develop its agricultural potential and it became an exporter of food. While industrialisation was taking off in the northern Spanish regions of Catalonia and the Basque country, Andalusia remained traditional and displayed a deep social division between a small class of wealthy landowners and a population made up largely of poor agricultural labourers and tradesmen.