Observational studies report that physical activity and metformin are associated with improved clinical outcome in patients with cancer. Inflammation is one biological mechanism hypothesized to mediate these associations. In this phase II, multicenter, 2 × 2 factorial trial, 139 patients with breast and colorectal cancer who completed standard therapy were randomized to one of four treatment groups for 12 weeks: exercise alone, metformin alone, exercise and metformin, or control. Inflammation outcomes included high-sensitivity C-reactive protein (hs-CRP), soluble tumor necrosis factor alpha receptor two (sTNFαR2), and IL6. The primary modeling strategy evaluated the trial product estimand that was quantified using a generalized linear mixed model. Compared with control, exercise alone reduced hs-CRP [-30.2%; 95% confidence interval (CI), -50.3, -1.0] and IL6 (-30.9%; 95% CI, -47.3, -9.5) but did not change sTNFαR2 (1.0%; 95% CI, -10.4, 13.9). Compared with control, metformin alone did not change hs-CRP (-13.9%; 95% CI, -40.0, 23.4), sTNFαR2 (-10.4%; 95% CI, -21.3, 2.0), or IL6 (-22.9%; 95% CI, -42.3, 2.0). Compared with control, exercise and metformin reduced sTNFαR2 (-13.1%; 95% CI, -22.9, -1.0) and IL6 (-38.7%; 95% CI, -52.3, -18.9) but did not change hs-CRP (-20.5%; 95% CI, -44.0, 12.7). The combination of exercise and metformin was not synergistic for hs-CRP, sTNFαR2, or IL6. In survivors of breast and colorectal cancer with low baseline physical activity and without type 2 diabetes, exercise and metformin reduced measures of inflammation that are associated with cancer recurrence and mortality.