Preservatives, such as isothiazolinones and formaldehyde-releasing compounds, provide safety and stability in consumer products by preventing microbial contamination. Yet these ingredients present human and environmental hazards, including allergic contact dermatitis and aquatic toxicity. The development of safer alternatives has been stymied by trade-offs between safety and efficacy. To enable the identification of safer preservatives, substances from eight functional classes were assessed for antimicrobial efficacy and human and environmental hazards. First, 130 substances were evaluated for microbial inhibitory activity against two relevant model microorganisms, Aspergillus brasiliensis (filamentous fungi) and Pseudomonas aeruginosa (Gram-negative bacteria). High-performing compounds within each class were assessed for hazards across a broad suite of human and environmental health end points. Four promising compounds were selected for further testing based on microbial inhibition, hazard profiles, and commercial availability. These ingredients were tested for biocidal activity in model home care formulations using methods adapted from industrial preservative challenge guidelines (USP-51). Two substances were identified, caprylhydroxamic acid and caprylyl glycol, that provided adequate preservation and improved toxicity profiles compared to isothiazolinone and formaldehyde-releasing preservatives. This study highlights trade-offs between antimicrobial activity and hazards across a broad spectrum of chemical classes relevant to safer preservative development.