In the analysis of polystyrene nanoplastics (PSNs), a nonpolar polymer (NP), using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), silver salts were used as cationization reagents and simultaneously brought the potential problems of silver clusters that interfered with the PSN signal of MS. To detect PSNs, silver trifluoroacetate (AgTFA) and silver nitrate (AgNO₃) were mixed with five polar matrices, namely 2-(4-hydroxyphenylazo) benzoic acid (HABA), dithranol (DI), sinapic acid (SA), trans-3-indoleacrylic acid (IAA), and 2,5-dihydroxybenzoic acid (DHB), and three nonpolar matrices, namely pyrene (PRN), anthracene (ATH) and acenaphthene (ACTH). The results showed that silver salt cluster ions were detected in the range of m/z 1000–4000. Five polar matrices with silver salts produced silver clusters, which interfered with the signals in the mass spectrum of PSNs, but the combination of these matrices with copper II chloride (CuCl₂) salt did not produce copper-related clusters. However, the use of nonpolar matrices such as PRN, ATH or ACTH significantly decreased the signals of silver salt cluster ions, and this alteration of matrix types is considered a promising optimization approach for silver cluster ions. The nonpolar matrix conditions were optimized without producing silver cluster ions and the optimal detection conditions were found to be under nonpolar matrices (e.g., pyrene) with silver salts (e.g., AgTFA). The results suggest that when polar matrices, such as HABA, DI, SA, IAA, and DHB, are combined with silver salts in MALDI-TOF-MS analysis, silver-related clusters are detected in the range of m/z 1000–4000. Inhibition of the production of silver cluster ions can be achieved by the use of a nonpolar matrix (e.g., PRN) or polar matrix (e.g., DHB) with copper salts.