Background Mental disorders are a leading cause of distress and disability worldwide. To meet patient demand, there is a need for increased access to high-quality, evidence-based mental health care. Telehealth has become well established in the treatment of illnesses, including mental health conditions. Objective This study aims to conduct a robust evidence synthesis to assess whether there is evidence of differences between telehealth and face-to-face care for the management of less common mental and physical health conditions requiring psychotherapy. Methods In this systematic review, we included randomized controlled trials comparing telehealth (telephone, video, or both) versus the face-to-face delivery of psychotherapy for less common mental health conditions and physical health conditions requiring psychotherapy. The psychotherapy delivered had to be comparable between the telehealth and face-to-face groups, and it had to be delivered by general practitioners, primary care nurses, or allied health staff (such as psychologists and counselors). Patient (symptom severity, overall improvement in psychological symptoms, and function), process (working alliance and client satisfaction), and financial (cost) outcomes were included. Results A total of 12 randomized controlled trials were included, with 931 patients in aggregate; therapies included cognitive behavioral and family therapies delivered in populations encompassing addiction disorders, eating disorders, childhood mental health problems, and chronic conditions. Telehealth was delivered by video in 7 trials, by telephone in 3 trials, and by both in 1 trial, and the delivery mode was unclear in 1 trial. The risk of bias for the 12 trials was low or unclear for most domains, except for the lack of the blinding of participants, owing to the nature of the comparison. There were no significant differences in symptom severity between telehealth and face-to-face therapy immediately after treatment (standardized mean difference [SMD] 0.05, 95% CI −0.17 to 0.27) or at any other follow-up time point. Similarly, there were no significant differences immediately after treatment between telehealth and face-to-face care delivery on any of the other outcomes meta-analyzed, including overall improvement (SMD 0.00, 95% CI −0.40 to 0.39), function (SMD 0.13, 95% CI −0.16 to 0.42), working alliance client (SMD 0.11, 95% CI −0.34 to 0.57), working alliance therapist (SMD −0.16, 95% CI −0.91 to 0.59), and client satisfaction (SMD 0.12, 95% CI −0.30 to 0.53), or at any other time point (3, 6, and 12 months). Conclusions With regard to effectively treating less common mental health conditions and physical conditions requiring psychological support, there is insufficient evidence of a difference between psychotherapy delivered via telehealth and the same therapy delivered face-to-face. However, there was no includable evidence in this review for some serious mental health conditions, such as schizophrenia and bipolar disorders, and further high-quality research is needed to determine whether telehealth is a viable, equivalent treatment option for these conditions.