Surface water is exposed to contaminants which change the natural hydrological parameters and consequent contaminant dispersion. Water self-depuration is an ecological process aiming to restore the natural watercourse balance, which depends on the quality and quantity of topical and diffuse contributions. The main goal of this research is the evaluation of surface water quality in the Agueda River (Portugal-Spain transboundary watershed) and its self-depuration ability considering different predicted scenarios. Biochemical oxygen demand (BOD5), dissolved oxygen (DO), dry residue, Ptotal, Ntotal, pH, temperature and microbiological parameters were analyzed, in thirty-six surface water samples. Simulation of different quality scenarios was undertaken using Qual2Kw software and the river's self-depuration ability discussed. The obtained model's calibration achieved a score of 95% confidence interval, for almost analyzed parameters. The calibrated model was used for two prediction scenario construction. The first one, intending to assess the influence of topical contaminated discharge and the second one, aiming to evaluate the influence of minimum flow rates, representing an extremely dry year. The two considered scenarios revealed that self-depuration capacity is more affected by the presence of minimum flow rates than topical discharges, attesting a large potential for self-depuration along the Agueda River.