Background: Acupressure has been used to manage agitation in people with dementia because it is safe and inexpensive. However, its effect on agitation and at the biochemical level is uncertain. Methods: This randomized controlled trial examined the effect of acupressure on agitation, as measured by the Cohen-Mansfield Agitation Inventory (CMAI); and on salivary cortisol, as measured at baseline (T0) and in the 3rd (T1), 5th (T2), and 8th (T3) weeks. There were 119 agitated residents with dementia randomized into 3 groups: acupressure (n = 39), sham (n = 41), and usual-care group (n = 39). Results: A downward trend in agitation over time was noted in the acupressure group, which almost reached a level of significance in interaction effects between groups and time points (p = 0.052). Post hoc pairwise tests in the acupressure group showed that acupressure significantly reduced agitation at T2 (mean difference -6.84, 95% CI -10.60, -3.08) compared to baseline. Significant interaction effects between groups and time points were observed on the level of salivary cortisol (p = 0.022). Conclusion: Acupressure is a multicomponent intervention that can reduce agitation. Acupoint activation may not be a significant component in reducing agitation, although this result may have been limited by the inadequate sample size. Acupressure is effective in reducing salivary cortisol in people with dementia.