Laser ablation inductively coupled plasma–mass spectrometry (LA-ICP-MS) is applied for the quantitative determination of manganese concentration in metal samples. A set of Certified Reference Materials, with different matrix elements (Fe, Cu, Ni, Co, Al) and with certified Mn values, were analyzed. Absorption and plasma break-down depend on the solid phase; as a result, there are differences in mass ablation rates that influence the Mn signal response. In order to be able to compare Mn signals, the relative element-dependent response of tested metal matrices was determined from the ablation of Fe, Cu, Ni, Co, and Al pure metal targets. Relative sensitivity factors (RSFs), calculated as the ratio of the signal intensity of 59Co, 58Ni, 63Cu, and 27Al to the signal intensity of 56Fe, were: 0.79, 0.71, 0.74, and 0.51, respectively. All the isotope signals were matched to the value that should correspond to the relative abundance of 56Fe (91.75%). These experimentally determined RSFs were applied for compensating the observed differences. For quantitative measurements a set of CRM carbon steel samples (SS-451/1 to SS-460/1), with Fe contents of approximately 98%, was used for calibration. The samples with different matrices were measured using the main matrix element as internal standard; for this purpose, the measured intensity was firstly extrapolated, from their content in the sample, to the value that should correspond to a content of 98% and, after, was corrected with the calculated RSF. The developed quantification approach provides manganese results with deviations of 5–10% from the certified values, with relative standard deviations of 3–8%.