Purpose: There is a paucity of literature identifying factors that influence the back and neck pain (BNP)–workplace absenteeism relationship. Therefore, this study aimed to investigate the association between BNP and workplace absenteeism and potential mediating variables in a large sample of the US population. Methods: Nationally representative data collected in 2019 from the RAND American Life Panel (ALP) were used for this retrospective study. Workplace absenteeism was defined as the number of days of absence in the past 12 months for health-related reasons (count variable), while BNP corresponded to the presence of back pain due to spinal stenosis, back pain due to other causes, or neck pain (dichotomous variable). Control variables included sex, age, ethnicity, marital status, education, occupation, annual family income, health insurance, obesity, and diabetes. There were eight influential variables (depression, anxiety, sleep disorder, alcohol dependence, opioid dependence, walking difficulty, standing difficulty, and sitting difficulty). The association between BNP and workplace absenteeism was analyzed using a negative binomial regression model. Results: There were 1,471 adults aged 22–83 years included in this study (52.9% of men; mean [standard deviation] age 44.5 [13.0] years). After adjusting for control variables, BNP was positively and significantly associated with workplace absenteeism (incidence rate ratio = 1.40, 95% confidence interval: 1.07–1.83). Walking, standing, and sitting difficulties individually explained between 24 and 43% of this association. Conclusions: Workplace interventions focusing on the management of BNP and overcoming difficulties in walking, standing, and sitting, potentially utilizing exercise, therapy, and ergonomic interventions, may prevent absenteeism.