This study investigated the effect of silver diamine fluoride (SDF) and potassium iodide (KI) treatment on secondary caries prevention and tooth discolouration in glass ionomer cement (GIC) restoration. Cervical GIC restorations were done on 30 premolars with: Group 1, SDF + KI; Group 2, SDF (positive control); Group 3, no treatment (negative control). After cariogenic biofilm challenge, the demineralisation of dentine adjacent to the restoration was evaluated using micro-computed tomography (micro-CT) and Fourier transform infrared (FTIR) spectroscopy. The colour of dentine adjacent to the restoration was assessed using CIELAB system at different time points. Total colour change (∆E) was calculated and was visible if ∆E > 3.7. Micro-CT showed the outer lesion depths for Groups 1, 2 and 3 were 91 ± 7 µm, 80 ± 7 µm and 119 ± 8 µm, respectively (p < 0.001; Group 2 < Group 1 < Group 3). FTIR found that there was a significant difference in amide I-to-hydrogen phosphate ratio among the three groups (p < 0.001; Group 2 < Group 1 < Group 3). ∆E of Groups 1, 2 and 3 after biofilm challenge were 22.5 ± 4.9, 70.2 ± 8.3 and 2.9 ± 0.9, respectively (p < 0.001; Group 3 < Group 1 < Group 2). SDF + KI treatment reduced secondary caries formation on GIC restoration, but it was not as effective as SDF treatment alone. Moreover, a perceptible staining on the restoration margin was observed, but the intensity of discolouration was less than that with solely SDF treatment.