A single workflow based on three approaches (target, suspected and non-target screening) using liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS) in data independent acquisition mode (DIA) was developed to assess the presence of emerging pollutants (EPs) in water and sediments from a Mediterranean River Basin. Identification of potential contaminants was based on mass accuracy, isotopic ratio pattern, theoretical fragmentation, and retention time using Waters UNIFI software. In the suspect screening against a library containing 2200 components, 68 contaminants were tentatively identified, 6 of which were confirmed and quantified with analytical standards. Non-target screening (NTS) required additional manual processing and the aid of an on-line database (ChemSpider) to tentatively identify compounds. Eprosartan, an antihypertensive drug not included in the library used for suspected screening, was confirmed and semi-quantified. The identification of Eprosartan proved the workflow to be functional for NTS. Target screening of 171 pesticides and 33 pharmaceuticals and personal care products (PPCPs) including the compounds confirmed using suspect (6) and non target (1) screening achieved monitoring of the most abundant contaminants from the head to the mouth of the Turia basin to establish their spatial distribution. QTOF-MS screening versatility with its high-resolution capability allows for a comprehensive assessment of EPs in the aquatic environment.