Suspect screening using liquid chromatography with high resolution mass spectrometry provides an opportunity for expanding the detection coverage of emerging contaminants in the environment. Screening workflows may suffer from high frequency of false positives or insufficient confidence in the identification of compounds; however, stringent criteria could lead to high false negatives. A workflow must have a balanced criteria, both selective and sensitive, to be able to identify real features without missing low abundant features traceable to analytes of interest. A highly selective (87%) and sensitive (97%) workflow was developed by characterizing the occurrence of contaminants in wastewater and surface water from Hong Kong, India, Philippines, Sweden, Switzerland, and the U.S. Sixty-eight contaminants were identified and confirmed with reference standards, including pharmaceuticals, pesticides, and industrial chemicals. The antimicrobials metronidazole, clindamycin, linezolid, and rifaximin were detected. Notably, antifungal compounds were detected in samples from six countries, with levels up to 1380 ng/L. Amoxicillin transformation products, penilloic acid (285–8047 ng/L) and penicilloic acid (107 ng/L), were confirmed for the first time with reference standards in wastewater samples from India, Sweden, and U.S. This workflow provides an efficient approach to broad-scale identification of emerging contaminants using publicly-available databases for suspect screening and prioritization.