Clinical trials have demonstrated traditional spa therapy effects in musculoskeletal disorders (MSDs). This is the first observational study in Italy aimed at evaluating in real-life the short-time effects of spa rehabilitation on pain, mood and quality of life (QoL) among degenerative or post-surgery MSDs patients. Through the involvement of six Italian spa facilities, 160 patients were enrolled; data from 123 patients were finally analysed. Seventy-nine patients (64.3%) accessed the spa for degenerative MSDs, while 44 (35.8%) had a post-surgical condition. All the patients included in the study underwent 12 sessions of water-based exercise (joint exercises, muscle strengthening, gait training, proprioceptive and balance techniques) conducted in thermal or in warm water pools, six sessions per week, for a period of 2 weeks from March 2019 up to October 2019. A group of 45 patients (36.6%) also received traditional thermal therapies, including 12 mud therapy sessions and 12 thermal baths, six times each week, for 2 weeks. Evaluation before and after the treatment included the Numerical Rating Scale (NRS), the Short Form Health Survey (SF-12) and the EuroQol-5D (EQ-5D). The analysis of the scores reported in the questionnaires after the treatment showed a significant improvement in all the scores evaluated. Comparison between patients that performed water-based exercise protocols alone (group A) and patients that in addition to water exercise performed traditional thermal interventions (group B) showed no statistically significant differences in NRSp, NRSa, NRSm, SF-12 PCS, SF-12 MCS and EQ-5D variations; only NRSa value reduction was lower in group B. Sulphate water was found to be associated with a lower reduction of all the scores considered, when compared to the other water types. Patients with degenerative or post-surgery MSDs showed favourable effects on pain, mood and QoL after water exercise training alone or in combination with traditional thermal therapy. Our research provides the first proof that spa rehabilitation can be in real-life conditions an appropriate alternative strategy for post-orthopaedic surgical outcomes recovery. In the future, these results will need to be further investigated.