The oil-field water in Nanyi Mountain, located in the west of Qaidam Basin of Qinghai-Tibet Plateau, is rich in lithium, calcium and other components. Thus, it was difficult to determine the exact content of lithium due to the matrix interference problems using traditional flame atomic absorption spectrometry, especially in the process of different evaporation stages. Though the general matrix matching method can resolve this issue, it was tedious and time-consuming. In this work, DOE was applied to study the influences of main coexisting ions, and the flame atomic absorption spectrometry was optimized based on the analysis of main coexisting elements, releasing agent selection as well as the establishment of the interference model. The results indicated that Ca2+, Sr2+, Mg2+, Na+ and Ca2+*B had the significant interferences on lithium determination, and the sequencing was Ca2+＞Sr2+＞Mg2+＞Ca2+*B＞Na+. The comparative study suggested that potassium oxalate showed excellent performances as the releasing agent to eliminate the influences of Ca2+, Sr2+, Mg2+, Na+ and Ca2+*B. And The relative error of lithium determination was reduced from -20.75% to -12.15% Meanwhile, results showed the response surface experimental design was beneficial to eliminate the influences of Na+, which was proved by the variance analysis and fitting degree analysis. In order to verify the conclusion further, different kinds of oil-field water were used. The results manifested the standard recovery of lithium was 89.30%~98.60% after adding potassium oxalate as the releasing agent, and the standard recovery increased to 98.88%~101.40% after the correction using the sodium interference model. All of the data indicated that the accuracy of lithium determination was improved greatly. The optimized method was not only applicable to the whole separation process of the oil-field water in Nanyi Mountain, but also applicable to other brines. And it proposed a guideline for the accurate determination of lithium for enterprises.