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The purpose of the study was to investigate a novel BRAF and CDK 4/6 inhibitor combination therapy in a murine model of BRAF-V600-mutant human melanoma monitored by 18F–FDG-PET/CT and diffusion-weighted MRI (DW-MRI). Human BRAF-V600-mutant melanoma (A375) xenograft-bearing balb/c nude mice (n= 21) were imaged by 18F–FDG-PET/CT and DW-MRI before (day 0) and after (day 7) a 1-week BRAF and CDK 4/6 inhibitor combination therapy (n= 12; dabrafenib, 20 mg/kg/d; ribociclib, 100 mg/kg/d) or placebo (n= 9). Animals were scanned on a small animal PET after intravenous administration of 20 MBq 18F–FDG. Tumor glucose uptake was calculated as the tumor-to-liver-ratio (TTL). Unenhanced CT data sets were subsequently acquired for anatomic coregistration. Tumor diffusivity was assessed by DW-MRI using the apparent diffusion coefficient (ADC). Anti-tumor therapy effects were assessed by ex vivoimmunohistochemistry for validation purposes (microvascular density – CD31; tumor cell proliferation – Ki-67). Tumor glucose uptake was significantly suppressed under therapy (∆TTLTherapy− 1.00 ± 0.53 vs. ∆TTLControl0.85 ± 1.21; p< 0.001). In addition, tumor diffusivity was significantly elevated following the BRAF and CDK 4/6 inhibitor combination therapy (∆ADCTherapy0.12 ± 0.14 × 10−3mm2/s; ∆ADCControl− 0.12 ± 0.06 × 10−3mm2/s; p< 0.001). Immunohistochemistry revealed a significant suppression of microvascular density (CD31, 147 ± 48 vs. 287 ± 92; p= 0.001) and proliferation (Ki-67, 3718 ± 998 vs. 5389 ± 1332; p= 0.007) in the therapy compared to the control group. A novel BRAF and CDK 4/6 inhibitor combination therapy exhibited significant anti-angiogenic and anti-proliferative effects in experimental human melanomas, monitored by 18F–FDG-PET/CT and DW-MRI.