Systemic Sclerosis (SSc) is an autoimmune disease characterized by a triad of inflammation, vasculopathy, and fibrosis of the skin and internal organs such as gastrointestinal tract, heart, lungs, and kidneys. SSc can lead to premature death especially when there is cardiopulmonary involvement. At early stages, SSc is characterized by an alteration of blood vessel network and hypoxia in the fingertip. Imaging these parameters could lead to early diagnosis of SSc patients. In this study, we investigated the feasibility to detect and diagnose SSc by imaging the oxygen saturation in the nail-bed using photoacoustics (PA) and estimating skin thickening using high-frequency ultrasound (HFUS). Thirty-one subjects (adult man and women) participated in this study: 12 patients with systemic sclerosis, 5 patients with early systemic sclerosis, 5 subjects with primary Raynaud’s phenomenon, and 9 healthy volunteers. The measurements showed that both the nail bed oxygen saturation (77.9% ±10.5 vs. 94.8% ±2.8, p < 0.0001) and the skin thickness (0.51 ±0.17 mm vs. 0.31 ±0.06 mm, p<0.005) of patients with SSc was significantly different compared to healthy volunteers. Most importantly the measurements showed a significant difference between early SSc and primary Raynaud’s phenomenon for both oxygen saturation (80.8 ± 8.1% vs. 93.9 ± 1.1%) and skin thickness (0.48 ± 0.06 mm vs. 0.27 ± 0.01 mm). The PA and HFUS data was supported by conventional capillaroscopy imaging performed on all participants. This pilot study demonstrates the possibility to use photoacoustics and high-frequency ultrasound as a diagnostic tool for early detection of systemic sclerosis.