Polypharmacy is associated with poorer self-rated health (SRH). However, whether polypharmacy has an impact on the SRH progression is unknown. This study investigates the association of polypharmacy with SRH change in 1428 participants of the Berlin Initiative Study aged 70 years and older over four years. Polypharmacy was defined as the intake of ≥5 medications. Descriptive statistics of SRH-change categories stratified by polypharmacy status were reported. The association of polypharmacy with being in SRH change categories was assessed using multinomial regression analysis. At baseline, mean age was 79.1 (6.1) years, 54.0% were females, and prevalence of polypharmacy was 47.1%. Participants with polypharmacy were older and had more comorbidities compared to those without polypharmacy. Over four years, five SRH-change categories were identified. After covariate adjustment, individuals with polypharmacy had higher odds of being in the stable moderate category (OR 3.55; 95% CI [2.43–5.20]), stable low category (OR 3.32; 95% CI [1.65–6.70]), decline category (OR 1.87; 95% CI [1.34–2.62]), and improvement category (OR 2.01; [1.33–3.05]) compared to being in the stable high category independent of the number of comorbidities. Reducing polypharmacy could be an impactful strategy to foster favorable SRH progression in old age.