Objectives: Our study aimed to assess the associations between meal-replacement (MR) drinking and risks of all-cause, cardiovascular and cerebrovascular disease (CVD), and cancer mortality. Methods: The study was based on 6770 adults aged 20 years or older from the National Health and Nutrition Examination (NHANES) 2003–2006 with linked mortality data from the National Death Index for linked mortality records (until 31 December 2019). Respondents were categorized into four groups according to the frequency of MR drinking: ≤1 time per month (seldom), 2–3 times per month (monthly), 1–6 times per week (weekly), and ≥1 time per day (daily). The adjusted hazard ratios (aHRs) of MR drinking with all-cause, CVD, and cancer mortality were estimated by Cox proportional hazards regression models. Likelihood ratio tests were used to find potential interactions of MR drinking with age, sex, and BMI. Results: During a median follow-up of 14.4 years, a total of 1668 death events were recorded among the study population. Compared to respondents who seldom drank MR, daily and weekly drinkers had greater risks of all-cause mortality (aHRs and 95% confidence intervals [CI]: 1.52 [1.17–1.97] for daily; 1.54 [1.24–1.91] for weekly). Stratified analyses indicated that the effects of MR on all-cause mortality were different between females and males and were more substantial among females (P for interaction: 0.003; daily female drinkers vs. daily male drinkers: 2.01 [1.40–2.90] vs. 1.24 [0.85–1.81]; weekly female drinkers vs. weekly male drinkers: 1.68 [1.26–2.24] vs. 1.36 [0.97–1.91]). Conclusions: Daily and weekly MR drinking might increase the risk of all-cause mortality.