After the fall of Angkor in 1431, the center of Khmer power transitioned to a new location. King Ponhea Yat abandoned Angkor and established a new capital in Phnom Penh. Although Thai records indicate that the capital may have temporarily returned to Angkor around 1467, by the early 1500s, King Ang Chan (1505/1516–56) had firmly set his court in Lovek. During this period, while the Thais were engaged in repelling Burmese invasions, Ang Chan amassed an army and successfully reclaimed lost territories, including Pursat and Battambang.

The 16th century marked the arrival of Western missionaries and explorers in Cambodia. Despite the missionaries’ failure to convert locals, some explorers, such as the Spanish adventurers Blas Ruiz and Diogo Veloso, became influential figures in the Khmer court. Their expertise in firearms led to marriages with Cambodian princesses and positions as provincial governors under King Satha (1575–94). Reports from Spanish and Portuguese colonials in the Philippines and Malacca describe multicultural trading hubs in Lovek and Phnom Penh, featuring communities of Chinese, Arabs, Japanese, Spanish, and Portuguese. These towns became the most prosperous in the region, engaging in trade of gold, animal skins, ivory, silk, and precious stones.

However, the Khmer court faced continuous threats from the Thais. King Satha sought assistance from the Spanish in the Philippines, but this aid never materialized. Consequently, Satha fled to Laos, where he died, while Lovek was sacked by Thai forces in 1594. Following this, Cambodia experienced rapid changes in leadership, with King Chey Chettha establishing a new capital at Oudong, situated between Lovek and Phnom Penh, where it would remain for approximately two centuries.

By the late 17th century, the Vietnamese began their expansion southward into Champa and the Mekong Delta, further encroaching on Cambodia. The Khmer royal family, now divided into pro-Vietnamese and pro-Thai factions, faced increasing instability as the crown frequently changed hands.

In 1767, tensions escalated when a Thai prince sought refuge in Cambodia with plans to form a government in exile. This prompted Thai General Taksin to invade, leading to the destruction of Phnom Penh and decades of Thai control over Cambodia. The Thais installed a young prince, Ang Eng (r. 1779–97), on the throne under a Thai regent. To solidify their influence, they took Ang Eng to Bangkok for four years. Upon his return, he established himself in Oudong, where he died in 1797, leaving four sons and a lineage that continues to this day.