Purpose Although schizophrenia can be treated effectively, acute aggravations and relapses occur often. Antipsychotic drug therapies are fairly effective for decreasing the rate of relapses in patients with schizophrenia. This study aimed to compare paliperidone palmitate and the second-generation oral antipsychotic drugs used to treat patients with schizophrenia in terms of medication adherence, side effects, and quality of life. Methods The study included 33 patients diagnosed with schizophrenia who were treated with paliperidone palmitate and 51 patients who were treated with second-generation oral antipsychotics. All the patients were administered the Positive and Negative Syndrome Scale, the Clinical Global Impression, the Extrapyramidal Symptom Rating Scale, the UKU (Ugvalg for Kliniske Undersgelser) Side Effect Rating Scale, the Short Form 36, the Morisky Medication Adherence Scale, and the Schedule for Assessing the Three Components of Insight. Results The medication adherence and perceived general health scores of the patients treated with paliperidone palmitate were significantly higher than those of the patients treated with second-generation antipsychotics, and the side effects of the medication on the patients' daily performance were significantly lower. Conclusions This study demonstrated that long-acting paliperidone palmitate therapy was associated with more favorable results in terms of medication adherence, drug side effects, and quality of life compared with second-generation oral antipsychotics. However, there is a need for further, more specific, and larger-scale studies in this field.