Background: Skeletal muscle loss is common in advanced cancer and is associated with negative outcomes. In malignant pleural mesothelioma (MPM), no study has reported body composition changes or factors associated with these changes. This study aimed to describe changes in body composition over time and its relationship with activity levels, dietary intake and survival. Methods: The study was a secondary analysis of data collected from a longitudinal observational study of patients with MPM. Participants completed 3-month assessments for up to 18 months. Participants with two dual-energy x-ray absorptiometry (DXA) scans were included. Changes in appendicular skeletal muscle mass (ASM) and total fat mass were used to categorise participants into phenotypes. Activity levels were measured with an ActiGraph GT3X+ accelerometer and energy and protein intake was measured with a 3-day food record and 24-h recall. Results: Eighteen participants were included (89% men, mean age 68.9 ± 7.1 years). Median time between DXA was 91 [IQR 84–118] days. Compared to participants with ASM maintenance (n = 9), fewer participants with ASM loss (n = 9) survived ≥12 months from follow-up (p = 0.002). Participants with ASM loss increased sedentary time (p = 0.028) and decreased light activity (p = 0.028) and step count (p = 0.008). Activity levels did not change in participants with ASM maintenance (p > 0.05). Energy and protein intake did not change in either group (p > 0.05). Conclusions: Muscle loss was associated with poorer survival and decreased activity levels. Interventions that improve physical activity or muscle mass could benefit patients with MPM.