Weight-loss maintenance is essential to sustain the health benefits of weight loss. Studies with lower intensity intervention supports under real-world conditions are lacking. This study examined changes in weight and cardiometabolic biomarkers among Spirited Life participants following initial 12-month weight loss at 12–24 months and 24–42 months. A total of 719 clergy received a wellness intervention, including a 10-week online weight-loss program in the first 12 months and monthly health coaching throughout 24 months. Mean changes in weight, blood pressure, high-density lipoproteins, and triglycerides were estimated using random effects linear models, accounting for repeated measures. Weight was additionally analyzed in subsamples stratified by body mass index (BMI). At baseline, 17.1% of participants had BMI < 25 kg/m2 and 11.8% had BMI ≥ 40 kg/m2. Mean 12-month weight loss was −2.4 kg (95% CI: −2.8 kg, −2.1 kg). On average, at 42 months, participants regained weight but did not exceed baseline (−0.5 kg, 95% CI: −1.2 kg, 0.2 kg), improvements in triglycerides were completely sustained (−13.9 mg/dL, 95% CI: −18.6 mg/dL, −9.2 mg/dL), and systolic blood pressure improvements remained significant (−1.9 mmHg, 95% CI: −3.0 mmHg, −0.9 mmHg). Participants with a BMI ≥ 40 kg/m2 lost significantly more weight that was sustained at 42 months (−5.8 kg, 95% CI: −8.9 kg, −2.7 kg). The Spirited Life wellness intervention produced weight loss and, for participants with higher levels of obesity, sustained weight-loss maintenance. The intervention was effective for long-term prevention of weight gain among participants with BMI of 25 to ≤40 kg/m2, through 42 months. Wellness interventions such as Spirited Life should be considered for adoption.