Background Individuals with comorbid posttraumatic stress disorder and major depressive disorder (PTSD‐MDD) often exhibit greater functional impairment and poorer treatment response than individuals with PTSD alone. Research has not determined whether PTSD‐MDD is associated with different network connectivity abnormalities than PTSD alone. Methods We used functional magnetic resonance imaging (fMRI) to measure resting state functional connectivity (rs‐FC) patterns of brain regions involved in fear and reward processing in three groups: patients with PTSD‐alone (n = 27), PTSD‐MDD (n = 21), and trauma‐exposed healthy controls (TEHCs, n = 34). Based on previous research, seeds included basolateral amygdala (BLA), centromedial amygdala (CMA), and nucleus accumbens (NAcc). Results Regardless of MDD comorbidity, PTSD was associated with decreased connectivity of BLA‐orbitalfrontal cortex (OFC) and CMA‐thalamus pathways, key to fear processing, and fear expression, respectively. PTSD‐MDD, compared to PTSD‐alone and TEHC, was associated with decreased connectivity across multiple amygdala and striatal‐subcortical pathways: BLA‐OFC, NAcc‐thalamus, and NAcc‐hippocampus. Further, while both the BLA‐OFC and the NAcc‐thalamus pathways were correlated with MDD symptoms, PTSD symptoms correlated with the amygdala pathways (BLA‐OFC; CMA‐thalamus) only. Conclusions Comorbid PTSD‐MDD may be associated with multifaceted functional connectivity alterations in both fear and reward systems. Clinical implications are discussed.