Multiple non-targeted analysis tools were used to look for a broad range of possible chemical contaminants present in surface and drinking water using liquid chromatography separation and high-resolution mass spectrometry detection, including both quadrupole time of flight (Q-ToF) and Orbitrap instruments. Two chromatographic techniques were evaluated on an LC-Q-ToF with electrospray ionization in both positive and negative modes: (1) the traditionally used reverse phase C18 and (2) the hydrophilic interaction liquid chromatography (HILIC) aimed to capture more polar contaminants that may be present in water. Multiple ionization modes were evaluated with an LC-Orbitrap, including electrospray (ESI) and atmospheric pressure chemical ionization (APCI), also in both positive and negative modes. A suspect screening library of over 1300 possible environmental contaminants, including pesticides, pharmaceuticals, personal care products, illicit drugs/drugs of abuse, and various anthropogenic markers was made with experimentally collected data with the LC-Q-ToF with both column types, with 227 chemicals being retained by the HILIC column. The non-targeted methods using multiple chromatographic and ionization modes were applied to environmental water samples collected with polar organic chemical integrative samplers (POCIS), including surface water upstream and downstream from wastewater effluent discharge, and the downstream drinking water intake and treated drinking water for three distinct sampling events. For the LC-Q-ToF, 442 chemical features were detected on the C18 column and 91 with the HILIC column in the POCIS extracts, while 556 features were found on the Orbitrap workflow by ESI and 131 features detected by APCI. Over 100 chemicals were tentatively identified by suspect screening and database searching. The comprehensive and systematic evaluation of these methods serve as a step in characterizing the chemical space covered when utilizing different chromatography and ionization methods, or different instrument workflows on complex environmental mixtures.