Older adults and patients with chronic disease presenting with muscle weakness or musculoskeletal disorders may benefit from low-load resistance exercise (LLRE) with blood flow restriction (BFR). LLRE-BFR has been shown to increase muscle size, strength, and endurance comparable to traditional resistance exercise but without the use of heavy loads. However, potential negative effects from LLRE-BFR present as a barrier to participation and limit its wider use. This study examined the perceptual, affective, and cardiovascular responses to a bout of LLRE-BFR and compared the responses to LLRE and moderate-load resistance exercise (MLRE). Twenty older adults (64.3 ± 4.2 years) performed LLRE-BFR, LLRE and MLRE consisting of 4 sets of leg press and knee extension, in a randomised crossover design. LLRE-BFR was more demanding than LLRE and MLRE through increased pain (p ≤ 0.024, d = 0.8–1.4) and reduced affect (p ≤ 0.048, d = −0.5–−0.9). Despite this, LLRE-BFR was enjoyed and promoted a positive affective response (p ≤ 0.035, d = 0.5–0.9) following exercise comparable to MLRE. This study supports the use of LLRE-BFR for older adults and encourages future research to examine the safety, acceptability, and efficacy of LLRE-BFR in patients with chronic disease.