Multiple LED-based spectral synthesis technology has been widely used in the fields of solar simulator, color mixing, and artificial lighting of plant factory and so on. Generally, amounts of LEDs are spatially arranged with compact layout to obtain the high power density output. Mutual thermal spreading among LEDs will produce the coupled thermal effect which will additionally increase the junction temperature of LED. Affected by the Photoelectric thermal coupling effect of LED, the spectrum of LED will shift and luminous efficiency will decrease. Correspondingly, the spectral synthesis result will mismatch. Therefore, thermal management of LED spatial layout plays an important role for multi-LEDs light source system. In the paper, the thermal dissipation network topology model considering the mutual thermal spreading effect among the LEDs is proposed for multi-LEDs system with various types of power. The junction temperature increment cased by the thermal coupling has the great relation with the spatial arrangement. To minimize the thermal coupling effect, an optimized method of LED spatial layout for the specific light source structure is presented and analyzed. The results showed that layout of LED with high-power are arranged in the corner and low-power in the center. Finally, according to this method, it is convenient to determine the spatial layout of LEDs in a system having any kind of light source structure, and has the advantages of being universally applicable to facilitate adjustment.