The potassium and lithium-rich brine is found in the central and northern part of Jiangling depression, while the southwest area is dominated by solid evaporites without potassium and lithium. This study aims to investigate the evolution of the paleo-saline lake brine in the southwestern Jiangling depression and sources of K and Li by the chemical composition of halite fluid inclusions of well ZK0303. Microscopic observations revealed the presence of primary fluid inclusions with chevron and cumulate structures in three groups of halite layers. The concentrations of Li, K, Mg, Ca, Br from the individual primary fluid inclusions were analyzed using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). According to the analysis of experimental data, the brine of Eocene halite fluid inclusion in the southwestern of the Jiangling depression is Na-K-Mg-Ca-Cl type, in which the highest concentration of K is 3 362.15 mg/L, and the highest concentration of Li is 15.10 mg/L. The relationship between Mg-Ca-2K of three halite layers in well ZK0303 shows that the brine of Eocene saline lake in the southwestern depression reached the stage of sylvite precipitation. The changes of each ion concentration of the three halite layers show that the degree of evaporation of Eocene saline lake had changed from low to high and then decreased. According to previous studies, the sources of Li and K in the brine are closely related to the basalt in the depression. However, the southwest area of the depression is far from the basalt distribution area, and it is difficult to obtain sufficient material supply. Lithium and K of the Eocene saline lake brine in this area may come from the dissolution of early halite in addition to evaporation.