Inconsistent results exist for whether or not weight cycling (WgtC) and weight variability (WgtV) increase mortality risk. The aim of this study was to examine the effect of WgtC and WgtV during adulthood on mortality risk. Data was obtained from the Women's Health Initiative (WHI) observational study (OS) dataset, acquired from the National Heart, Lung and Blood Institute (N = 47,473 overweight and obese women; age 50–79 years). Women were categorized (stable; WgtV: weight-gainer or loser; or WgtC) based on weight changes during early (18–35 years), mid (35–50 years), and late (50 years to current age) adulthood. Those with weight changes of <5% during all three time-periods were classified as being stable-weight. Weight-gainers were those with at least one period of weight-gain (≥5%) without a period of weight-loss (≥5%), and weight-losers were those with at least one period of loss without a period of gain during all time-periods. Those who experienced both a period of weight-gain and loss (≥5%) were categorized as WgtC. Compared to stable-weight individuals, WgtC and WgtV across adulthood were not significantly associated with mortality risk when the age-period of weight change was not considered. However, when considering the age period, increased mortality risk was observed for every 5 kg of weight-gain during early (hazard ratio (HR) = 1.04 (1.00–1.07)) or mid-adulthood (HR = 1.05 (1.02–1.08)), or for every 5 kg of weight-loss since mid (HR = 1.12 (1.01–1.24)) or late-adulthood (HR = 1.12 (1.04–1.20)). In conclusion, merely investigating WgtC and WgtV by weight changes across adulthood may not be sufficient to fully describe mortality risk, and the age at which the weight change occurred might be as important to consider.