The surgery of the impacted mandibular third molar is the most frequent procedure in dentistry. The prescription of systemic antibiotics after the third molar extraction is widespread among dentists, but this is still argumentative. This study is aimed at evaluating the postoperative effects of local antibiotic mixed with platelet-rich fibrin (PRF) and a postoperative systemic antibiotic prescribed for mandibular third molar surgery. The study included 75 patients divided into a control and 4 test groups ( n = 15 ). In the control group, only PRF was placed into the extracted socket, and no antibiotic was prescribed. In the first and third groups, PRF was applied to the socket; penicillin and clindamycin were prescribed as oral medications, respectively. In the second and fourth groups, only PRF combined with penicillin and clindamycin was applied into the socket, respectively. The outcome variables were pain, swelling, analgesic intake, and trismus. These variables were also assessed based on the first, second, third, and seventh days following the operation. Unpaired Student’s t -test and Mann–Whitney U test were used for analysis. There were significant differences in the total VAS pain scores between the control and group 3 ( p < 0.05 ), groups 1 and 2 ( p < 0.01 ), and group 4 ( p < 0.001 ) in ascending order. For analgesic intake, there was no significant difference for group 1 ( p > 0.05 ). However, there were statistical differences between the control group and groups 2 and 3 ( p < 0.01 ) and group 4 ( p < 0.001 ). Trismus and swelling did not differ among the groups ( p > 0.05 ). This study showed that the effects of local and systemic antibiotics with the use of PRF reduced postoperative outcomes. Moreover, local antibiotics with PRF may be a viable method to avoid the possible side effects of systemic antibiotics.