Purpose/Background Activating and sedating adverse effects of antipsychotics can be obstacles to their use. Methods/Procedures This study quantified the activating and sedating properties of first-line oral second-generation antipsychotics by examining the rates of adverse reactions as reported in product labeling for the indications of schizophrenia and adjunctive treatment of major depressive disorder. Additional data sources included regulatory documents, study synopses, and published study reports. Attributable risk increase and number needed to harm (NNH) were calculated for each agent versus placebo. Findings/Results Heterogeneity among the different antipsychotics regarding activating or sedating adverse events was observed, with some agents displaying the potential for both activating and sedating properties. For agents indicated for the treatment of schizophrenia, predominantly activating medications include lurasidone (NNH, 11 for akathisia vs 20 for somnolence) and cariprazine (NNH, 15 for akathisia vs 65 for somnolence-combined terms). Similarly activating and sedating are risperidone (NNH, 15 for akathisia vs 13 for sedation) and aripiprazole (NNH, 31 for akathisia vs 34 for somnolence). Predominantly sedating are olanzapine, quetiapine immediate and extended release, ziprasidone, asenapine, and iloperidone. Agents that are neither activating nor sedating are paliperidone and brexpiprazole. For major depressive disorder, the overall findings regarding activation and sedation appear similar to those seen with schizophrenia. Data extracted were limited to those available from registrational studies that contributed to the adverse event tables contained in the product labels. Postregistrational comparative studies may yield different outcomes. Implications/Conclusions Differences in tolerability profiles regarding activation and sedation have implications in terms of selecting the optimal antipsychotic for a given individual.