Abstract Background Chronic medical conditions (CMCs) often emerge and accumulate during the transition from mid- to late-life, and the resulting multimorbidity can greatly impact physical function. We assessed the association of CMC presence and incidence on trajectories of physical function from mid- to early late-life in the Study of Women’s Health Across the Nation. Methods Physical function was assessed at eight clinic visits (average 14 years follow-up) using the physical function subscale of the Short Form-36. CMCs included osteoarthritis, diabetes, stroke, hypertension, heart disease, cancer, osteoporosis, and depressive symptomatology, and were considered cumulatively. Repeated-measures Poisson models estimated longitudinal change (expressed as percent difference) in physical function by chronic CMCs. Change-points assessed physical function change coincident with the development of a new condition. Results Women (N = 2,283) followed from age 50.0 ± 2.7 to 64.0 ± 3.7 years; 7.3% had zero CMCs through follow-up, 22.5% (N = 513) had no baseline CMCs but developed ≥1, 22.7% women had ≥1 baseline CMC but never developed another, and 47.6% had ≥1 baseline CMC and developed ≥1 more. Each additional baseline CMC was associated with 4.0% worse baseline physical function and annual decline of 0.20%/year. Women with more baseline CMCs had greater decline in physical function with a new CMC (−1.90% per condition); and annual decline when developing a new condition accelerated by −0.33%/year per condition. Conclusions Self-reported physical function changes are evident from mid- to early late-life with the development of CMCs. Preventing or delaying CMCs may delay declines in physical function, and these potential pathways to disability warrant further research.