Depression that is resistant to two or more adequate treatment trials-treatment-resistant depression (TRD)-is a prevalent clinical challenge. Although psychotherapies have been recommended by clinical guidelines as an alternative or adjunctive treatment strategy, the effectiveness of psychotherapy in individuals with TRD has not yet been evaluated through meta-analytic methods, primarily due to a limited number of trials. This highlights the necessity of personalized research targeting this specific population. This systematic review and meta-analysis aimed to summarize the evidence on psychotherapy in treating TRD. A systematic search was conducted following the Guidelines from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Articles were included if they quantitatively examined the efficacy of psychotherapy on depression symptoms in individuals diagnosed with depression who had not responded to at least two prior treatments (i.e., pharmacotherapy and/or psychotherapy). A total of 12 studies were included. The quality of evidence was evaluated as being globally moderate. When pooling all psychotherapies, a small-to-moderate, but significant, effect on depressive symptoms was observed compared to the control group (SMD = -0.49, CI = -0.63; -0.34). The observed effect remained unchanged after removing the outlier (SMD = -0.47, CI = -0.62; -0.32). When examining depressive symptoms by type of psychotherapy, Mindfulness-Based Cognitive Therapy (SMD = -0.51, CI = -0.76; -0.25), Cognitive Behavioral Therapy (SMD = -0.53, CI = -0.92; -0.14), and Cognitive Therapy (SMD = -0.51, CI = -1.01; -0.01) showed a moderately significant effect on depressive symptoms compared to the control group. Although this potentially represents the first meta-analysis in this area, the number of studies specifically addressing this complex population remains limited, and the existing literature is still in its early stages. Research focusing on TRD is notably sparse compared to the broader body of work on depression without treatment resistance. Consequently, it was not possible to conduct meta-analyses by type of psychotherapy across all treatment modalities and by type of control group. Due to several study limitations, there is currently limited evidence available about the effectiveness of psychotherapy for TRD, and further trials are needed. Beyond the treatments usually offered for depression, it is possible that TRD requires a personalized medicine approach.