The growth and formation of primary intermetallics formed in Sn-3.5Ag soldered on copper organic solderability preservative (Cu-OSP) and electroless nickel immersion gold (ENIG) surface finish after multiple reflows were systematically investigated. Real-time synchrotron imaging was used to investigate the microstructure, focusing on the in situ growth behavior of primary intermetallics during the solid–liquid–solid interactions. The high-speed shear test was conducted to observe the correlation of microstructure formation to the solder joint strength. Subsequently, the experimental results were correlated with the numerical Finite Element (FE) modeling using ANSYS software to investigate the effects of primary intermetallics on the reliability of solder joints. In the Sn-3.5Ag/Cu-OSP solder joint, the well-known Cu6Sn5interfacial intermetallic compounds (IMCs) layer was observed in each reflow, where the thickness of the IMC layer increases with an increasing number of reflows due to the Cu diffusion from the substrate. Meanwhile, for the Sn-3.5Ag/ENIG solder joints, the Ni3Sn4interfacial IMC layer was formed first, followed by the (Cu, Ni)6Sn5IMC layer, where the formation was detected after five cycles of reflow. The results obtained from real-time imaging prove that the Ni layer from the ENIG surface finish possessed an effective barrier to suppress and control the Cu dissolution from the substrates, as there is no sizeable primary phase observed up to four cycles of reflow. Thus, this resulted in a thinner IMC layer and smaller primary intermetallics, producing a stronger solder joint for Sn-3.5Ag/ENIG even after the repeated reflow process relative to the Sn-3.5Ag/Cu-OSP joints.