Background: Knee osteoarthritis progression may be related to altered knee loads, particularly in those with varus malalignment. Using randomized controlled trial data, this secondary analysis of complete datasets (n = 67) compared the effects of a functional weightbearing (WB) and non-weightbearing quadriceps strengthening exercise (NWB) program on measures of medial tibiofemoral joint contact force (MTCF) during walking. Methods: Participants aged ≥50 years and with medial knee osteoarthritis and varus malalignment were randomly allocated to a 12-week, home-based, physiotherapist-prescribed exercise program comprised of WB exercises (n = 31), or NWB exercise (n = 36). Three-dimensional lower-body motion, ground reaction forces, and surface electromyograms from six lower-limb muscles were acquired during walking at baseline and at 12-weeks follow-up. An electromyogram-informed neuromusculoskeletal model estimated bodyweight (BW) normalized MTCF (peak and impulse), including external and muscular contributions to MTCF. Results: There was no between-group difference in the change in peak MTCF (−0.02 [−0.12, 0.09] BW) or MTCF impulse (−0.01 [−0.06, 0.03] BW·s). There was a between-group difference in the muscle contribution to peak MTCF (−0.08 [−0.15, −0.00] BW) and MTCF impulse (−0.04 [−0.08, −0.00] BW·s), whereby the muscle contribution reduced more in the NWB group over time compared to the WB group. There was also a between group-difference in the external contribution to peak MTCF (0.09 [0.01, 0.18] BW), but this reduced more in the WB group than in the NWB group. Conclusions: Our findings suggest no difference in MTCF between the two exercise programs, but differences in the contribution to MTCF between the two exercise programs were observed in those with medial knee osteoarthritis and varus malalignment.