Background: Monitoring population physical activity (PA) and sedentary behavior over time is important to guide public health actions. The objective of this study was to investigate the changes in PA and sedentary behavior of adult residents in Luxembourg over 10 years. We also investigated variations in change over time across sociodemographic subgroups. Methods: Two population-based cross-sectional studies of adults living in Luxembourg (Observation of Cardiovascular Risk Factors in Luxembourg [ORISCAV-LUX] [2007–2008] and ORISCAV-LUX 2 [2016–2018]) were considered. Multilevel mixed-effects models were used to investigate changes over time between the studies with regard to self-reported total PA (metabolic equivalent of task-min/week), PA levels (inactive/sufficiently active/highly active), total sitting time, recreational television viewing, and personal computer (PC) use outside of work (in minutes per day). Results: The ORISCAV-LUX study included 1318 participants and the ORISCAV-LUX 2 study involved 1477 participants; 573 adults took part in both studies. The proportion of participants categorized as highly active increased over time by 6.9%. Total PA (761 metabolic equivalent of task-min/wk), television viewing (12 min/d), and PC use outside of work (13 min/d) also increased, whereas the total sitting time decreased by 25 minutes per day. Variations in change over time were observed by sex, country of birth, education, employment status, and perceived financial difficulty. Conclusions: Over a 10-year period, PA increased and total sitting time decreased in adults living in Luxembourg. With regard to specific sedentary behaviors, television viewing, and PC use outside of work increased. Specific population subgroups will benefit the most from targeted efforts to increase PA and minimize sedentary behavior.